MENDELIAN

INHERITANCE

Mohammed El - KhateebJuly 11th 2012

MGL- 5

Genetic Diseases (GD)

Chromosomal Abnormalities

Single Gene Defects

Multifactorial Disorders

Non-Traditional Inheritance

Cancer Genetics

Topics of Discussion

bull Basic concepts of formal genetics

bull Autosomal dominant inheritance

bull Autosomal recessive inheritance

bull Factors that may complicate

inheritance patterns

bull Probability

Mendelian Inheritance

Single Gene Defects

Most common diams Autosomal recessive

diams Autosomal dominant

diams Factors complicating Mendelian inheritance

diams X-linked recessive

diams X-linked dominant

diams Y-linked

Pedigree

The family tree

Representation of the ancestry of an

individualrsquos family

Symbolic representations of family

relationships and inheritance of a trait

Prefix Autosomal X Linked Y Linked Mt Totals

Gene description 13554 661 48 35 14298+ Gene and phenotype

combined113 4 0 2 119

Phenotype

description molecular

basis known3518 277 4 28 3827

Phenotype

description or locus

molecular basis

unknown

1612 133 5 0 1750

Other mainly

phenotypes with

suspected mendelian

basis

1750 121 2 0 1873

Totals 20547 1196 59 65 21867

Number of Entries in OMIM (Updated 9 July 2013)

Genetic Diseases (GD)

Chromosomal Abnormalities

Single Gene Defects

Multifactorial Disorders

Non-Traditional Inheritance

Cancer Genetics

Topics of Discussion

bull Basic concepts of formal genetics

bull Autosomal dominant inheritance

bull Autosomal recessive inheritance

bull Factors that may complicate

inheritance patterns

bull Probability

Mendelian Inheritance

Single Gene Defects

Most common diams Autosomal recessive

diams Autosomal dominant

diams Factors complicating Mendelian inheritance

diams X-linked recessive

diams X-linked dominant

diams Y-linked

Pedigree

The family tree

Representation of the ancestry of an

individualrsquos family

Symbolic representations of family

relationships and inheritance of a trait

Prefix Autosomal X Linked Y Linked Mt Totals

Gene description 13554 661 48 35 14298+ Gene and phenotype

combined113 4 0 2 119

Phenotype

description molecular

basis known3518 277 4 28 3827

Phenotype

description or locus

molecular basis

unknown

1612 133 5 0 1750

Other mainly

phenotypes with

suspected mendelian

basis

1750 121 2 0 1873

Totals 20547 1196 59 65 21867

Number of Entries in OMIM (Updated 9 July 2013)

Topics of Discussion

bull Basic concepts of formal genetics

bull Autosomal dominant inheritance

bull Autosomal recessive inheritance

bull Factors that may complicate

inheritance patterns

bull Probability

Mendelian Inheritance

Single Gene Defects

Most common diams Autosomal recessive

diams Autosomal dominant

diams Factors complicating Mendelian inheritance

diams X-linked recessive

diams X-linked dominant

diams Y-linked

Pedigree

The family tree

Representation of the ancestry of an

individualrsquos family

Symbolic representations of family

relationships and inheritance of a trait

Prefix Autosomal X Linked Y Linked Mt Totals

Gene description 13554 661 48 35 14298+ Gene and phenotype

combined113 4 0 2 119

Phenotype

description molecular

basis known3518 277 4 28 3827

Phenotype

description or locus

molecular basis

unknown

1612 133 5 0 1750

Other mainly

phenotypes with

suspected mendelian

basis

1750 121 2 0 1873

Totals 20547 1196 59 65 21867

Number of Entries in OMIM (Updated 9 July 2013)

Mendelian Inheritance

Single Gene Defects

Most common diams Autosomal recessive

diams Autosomal dominant

diams Factors complicating Mendelian inheritance

diams X-linked recessive

diams X-linked dominant

diams Y-linked

Pedigree

The family tree

Representation of the ancestry of an

individualrsquos family

Symbolic representations of family

relationships and inheritance of a trait

Prefix Autosomal X Linked Y Linked Mt Totals

Gene description 13554 661 48 35 14298+ Gene and phenotype

combined113 4 0 2 119

Phenotype

description molecular

basis known3518 277 4 28 3827

Phenotype

description or locus

molecular basis

unknown

1612 133 5 0 1750

Other mainly

phenotypes with

suspected mendelian

basis

1750 121 2 0 1873

Totals 20547 1196 59 65 21867

Number of Entries in OMIM (Updated 9 July 2013)

Pedigree

The family tree

Representation of the ancestry of an

individualrsquos family

Symbolic representations of family

relationships and inheritance of a trait

Prefix Autosomal X Linked Y Linked Mt Totals

Gene description 13554 661 48 35 14298+ Gene and phenotype

combined113 4 0 2 119

Phenotype

description molecular

basis known3518 277 4 28 3827

Phenotype

description or locus

molecular basis

unknown

1612 133 5 0 1750

Other mainly

phenotypes with

suspected mendelian

basis

1750 121 2 0 1873

Totals 20547 1196 59 65 21867

Number of Entries in OMIM (Updated 9 July 2013)

Prefix Autosomal X Linked Y Linked Mt Totals

Gene description 13554 661 48 35 14298+ Gene and phenotype

combined113 4 0 2 119

Phenotype

description molecular

basis known3518 277 4 28 3827

Phenotype

description or locus

molecular basis

unknown

1612 133 5 0 1750

Other mainly

phenotypes with

suspected mendelian

basis

1750 121 2 0 1873

Totals 20547 1196 59 65 21867

Number of Entries in OMIM (Updated 9 July 2013)

Goals of Pedigree Analysis

bull Determine the mode of inheritance

dominant recessive partial

dominance sex-linked autosomal

mitochondrial maternal effect

bull Determine the probability of an

affected offspring for a given cross

Obtaining a pedigree

A three generation family history should be a standard component of medical practice Family history of the patient is usually summarized in the form of a pedigree

Points to remember

bull ask whether relatives have a similar problem

bull ask if there were siblings who have died

bull inquire about miscarriages neonatal deaths

bull be aware of siblings with different parents

bull ask about consanguinity

bull ask about ethnic origin of family branches

Pedigree

Symbols

Pedigree Analysis

Normal

Female

Normal

Male

Mating

1st born

Siblings

Affected

I

II

2 3

I

II

III

IV

2

1 2

1 2 3 4 5 6

1 2 3 4 5 6

1 2 3 4 5 6

Founders

ProbandIV - 2V

1 2

Autosomal dominant

inheritance

bull D abnormal gene

bull d normal gene

bull Each child of an

affected person has

a 50 chance of

being affected

bull Affected persons

are usually

heterozygous

Characteristics of autosomal dominant inheritance

1 A gene is dominant if it is expressed when heterozygous

2 An affected individual has a 50 chance of having an affected child

3 An affected child will have one affected parent

4 The affected parent can be either the mother or the father

5 Autosomal dominant traits have low frequencies in thepopulation

6 Autosomal dominant traits are usually lethal when homozygous

7 No skipping of generations

Autosomal Dominance

Waardenburg Syndrome

bull Hemizygous Having half the number

of alleles (eg males are hemizygous

for all X chromosome genes)

bull Expressivity The severity or intensity

of the phenotype of an allele

bull Penetrance The degree to which a

gene expresses any observable

phenotype

Pitfalls in Recognizing AD

Inheritancebull Incomplete Penetrance Some people who have the

gene mutation do not show the clinical effects

bull Penetrance Limited to one gender For example

when prostate cancer risk is inherited in an autosomal

dominant manner women who inherit the mutation are

not affected they can however pass the mutation on to

their sons

bull Variable Expressivity The gene mutation has variable

clinical manifestations the disorder may range from mild

to severe or a range of different complications may

occur among people with the mutation

Pitfalls in Recognizing AD

Inheritance

bull New Mutation An affected person may

be the first person in the family with the

condition due to a mutation arising for

the first time in sperm egg or embryo

bull Germline Mosaicism A new mutation

may arise in testis or ovary resulting in

an unaffected parent transmitting the

condition to two or more children

AD Disorders

Marfanrsquos Syndrome

Huntingtonrsquos Chorea

Osteogenesis imperfecta

Neurofibromatosis

Retinoblastoma

Tuberous sclerosis

Apertrsquos Syndrome

Multiple polyposis of colon

Achonroplacia

Brachydactylyl

Ehlers-Dalton Syndrome

Familial

Hypercholeserolemia

Porphyria

GENETIC TRAITS IN HUMANS CAN BE TRACKED

THROUGH FAMILY PEDIGREES

bull Recessive traits are often

more common in the

population than dominant

ones

bull Eg absence of freckles

more common than

presence

Polydactyly

Polydactaly

Autosomal Dominant Inheritance

Possible explanations for apparent

sporadic cases

bull Variable expressivity

bull New mutation

bull Non-penetrance

bull Gonadal mosaicism

Autosomal Recessive Carrier parents are

Heterozygotes carry the

recessive allele but exhibit

the wildtype phenotype

Normal parental phenotype

75 chance for normal

offspring

25 chance for affected

offspring

Males amp females equally

affected

ldquoInborn errors of metabolismrdquo

Associated with specific

ethnic groups

Unaffected parents have affected children

Affected individual has unaffected children

unless they marry a heterozygote or an

affected person

Sexes are affected equally

All normal children of an affected individual will

be heterozygotes or ldquocarriersrdquo

Often there has been a consanguineous

marriage

Autosomal recessive inheritance

Autosomal Recessive

Risks to children When both parents are carriers every child they have

has a 25 chance of being affected a 50 chance to

be a carrier and a 25 to neither be affected nor a

carrier

When one parent is a carrier and the other is not a

carrier or affected every child they have has a 50

chance to be a carrier and a 50 chance to neither be a

carrier nor affected No child will be affected

When one parent is affected and the other parent is a

carrier every child they have has a 50 chance to be

affected and a 50 chance to be a carrier

When one parent is affected and the other is not a

carrier or affected every child they have will be a

carrier No child will be affected

Heterozygote Advantage in Recessive Conditions

Condition Carriers protected against

1 Thalassaemia falciparum malaria

2 Sickle cell falciparum malaria

3 (G-6-PD deficiency

falciparum malaria)

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Obtaining a pedigree

A three generation family history should be a standard component of medical practice Family history of the patient is usually summarized in the form of a pedigree

Points to remember

bull ask whether relatives have a similar problem

bull ask if there were siblings who have died

bull inquire about miscarriages neonatal deaths

bull be aware of siblings with different parents

bull ask about consanguinity

bull ask about ethnic origin of family branches

Pedigree

Symbols

Pedigree Analysis

Normal

Female

Normal

Male

Mating

1st born

Siblings

Affected

I

II

2 3

I

II

III

IV

2

1 2

1 2 3 4 5 6

1 2 3 4 5 6

1 2 3 4 5 6

Founders

ProbandIV - 2V

1 2

Autosomal dominant

inheritance

bull D abnormal gene

bull d normal gene

bull Each child of an

affected person has

a 50 chance of

being affected

bull Affected persons

are usually

heterozygous

Characteristics of autosomal dominant inheritance

1 A gene is dominant if it is expressed when heterozygous

2 An affected individual has a 50 chance of having an affected child

3 An affected child will have one affected parent

4 The affected parent can be either the mother or the father

5 Autosomal dominant traits have low frequencies in thepopulation

6 Autosomal dominant traits are usually lethal when homozygous

7 No skipping of generations

Autosomal Dominance

Waardenburg Syndrome

bull Hemizygous Having half the number

of alleles (eg males are hemizygous

for all X chromosome genes)

bull Expressivity The severity or intensity

of the phenotype of an allele

bull Penetrance The degree to which a

gene expresses any observable

phenotype

Pitfalls in Recognizing AD

Inheritancebull Incomplete Penetrance Some people who have the

gene mutation do not show the clinical effects

bull Penetrance Limited to one gender For example

when prostate cancer risk is inherited in an autosomal

dominant manner women who inherit the mutation are

not affected they can however pass the mutation on to

their sons

bull Variable Expressivity The gene mutation has variable

clinical manifestations the disorder may range from mild

to severe or a range of different complications may

occur among people with the mutation

Pitfalls in Recognizing AD

Inheritance

bull New Mutation An affected person may

be the first person in the family with the

condition due to a mutation arising for

the first time in sperm egg or embryo

bull Germline Mosaicism A new mutation

may arise in testis or ovary resulting in

an unaffected parent transmitting the

condition to two or more children

AD Disorders

Marfanrsquos Syndrome

Huntingtonrsquos Chorea

Osteogenesis imperfecta

Neurofibromatosis

Retinoblastoma

Tuberous sclerosis

Apertrsquos Syndrome

Multiple polyposis of colon

Achonroplacia

Brachydactylyl

Ehlers-Dalton Syndrome

Familial

Hypercholeserolemia

Porphyria

GENETIC TRAITS IN HUMANS CAN BE TRACKED

THROUGH FAMILY PEDIGREES

bull Recessive traits are often

more common in the

population than dominant

ones

bull Eg absence of freckles

more common than

presence

Polydactyly

Polydactaly

Autosomal Dominant Inheritance

Possible explanations for apparent

sporadic cases

bull Variable expressivity

bull New mutation

bull Non-penetrance

bull Gonadal mosaicism

Autosomal Recessive Carrier parents are

Heterozygotes carry the

recessive allele but exhibit

the wildtype phenotype

Normal parental phenotype

75 chance for normal

offspring

25 chance for affected

offspring

Males amp females equally

affected

ldquoInborn errors of metabolismrdquo

Associated with specific

ethnic groups

Unaffected parents have affected children

Affected individual has unaffected children

unless they marry a heterozygote or an

affected person

Sexes are affected equally

All normal children of an affected individual will

be heterozygotes or ldquocarriersrdquo

Often there has been a consanguineous

marriage

Autosomal recessive inheritance

Autosomal Recessive

Risks to children When both parents are carriers every child they have

has a 25 chance of being affected a 50 chance to

be a carrier and a 25 to neither be affected nor a

carrier

When one parent is a carrier and the other is not a

carrier or affected every child they have has a 50

chance to be a carrier and a 50 chance to neither be a

carrier nor affected No child will be affected

When one parent is affected and the other parent is a

carrier every child they have has a 50 chance to be

affected and a 50 chance to be a carrier

When one parent is affected and the other is not a

carrier or affected every child they have will be a

carrier No child will be affected

Heterozygote Advantage in Recessive Conditions

Condition Carriers protected against

1 Thalassaemia falciparum malaria

2 Sickle cell falciparum malaria

3 (G-6-PD deficiency

falciparum malaria)

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Pedigree

Symbols

Pedigree Analysis

Normal

Female

Normal

Male

Mating

1st born

Siblings

Affected

I

II

2 3

I

II

III

IV

2

1 2

1 2 3 4 5 6

1 2 3 4 5 6

1 2 3 4 5 6

Founders

ProbandIV - 2V

1 2

Autosomal dominant

inheritance

bull D abnormal gene

bull d normal gene

bull Each child of an

affected person has

a 50 chance of

being affected

bull Affected persons

are usually

heterozygous

Characteristics of autosomal dominant inheritance

1 A gene is dominant if it is expressed when heterozygous

2 An affected individual has a 50 chance of having an affected child

3 An affected child will have one affected parent

4 The affected parent can be either the mother or the father

5 Autosomal dominant traits have low frequencies in thepopulation

6 Autosomal dominant traits are usually lethal when homozygous

7 No skipping of generations

Autosomal Dominance

Waardenburg Syndrome

bull Hemizygous Having half the number

of alleles (eg males are hemizygous

for all X chromosome genes)

bull Expressivity The severity or intensity

of the phenotype of an allele

bull Penetrance The degree to which a

gene expresses any observable

phenotype

Pitfalls in Recognizing AD

Inheritancebull Incomplete Penetrance Some people who have the

gene mutation do not show the clinical effects

bull Penetrance Limited to one gender For example

when prostate cancer risk is inherited in an autosomal

dominant manner women who inherit the mutation are

not affected they can however pass the mutation on to

their sons

bull Variable Expressivity The gene mutation has variable

clinical manifestations the disorder may range from mild

to severe or a range of different complications may

occur among people with the mutation

Pitfalls in Recognizing AD

Inheritance

bull New Mutation An affected person may

be the first person in the family with the

condition due to a mutation arising for

the first time in sperm egg or embryo

bull Germline Mosaicism A new mutation

may arise in testis or ovary resulting in

an unaffected parent transmitting the

condition to two or more children

AD Disorders

Marfanrsquos Syndrome

Huntingtonrsquos Chorea

Osteogenesis imperfecta

Neurofibromatosis

Retinoblastoma

Tuberous sclerosis

Apertrsquos Syndrome

Multiple polyposis of colon

Achonroplacia

Brachydactylyl

Ehlers-Dalton Syndrome

Familial

Hypercholeserolemia

Porphyria

GENETIC TRAITS IN HUMANS CAN BE TRACKED

THROUGH FAMILY PEDIGREES

bull Recessive traits are often

more common in the

population than dominant

ones

bull Eg absence of freckles

more common than

presence

Polydactyly

Polydactaly

Autosomal Dominant Inheritance

Possible explanations for apparent

sporadic cases

bull Variable expressivity

bull New mutation

bull Non-penetrance

bull Gonadal mosaicism

Autosomal Recessive Carrier parents are

Heterozygotes carry the

recessive allele but exhibit

the wildtype phenotype

Normal parental phenotype

75 chance for normal

offspring

25 chance for affected

offspring

Males amp females equally

affected

ldquoInborn errors of metabolismrdquo

Associated with specific

ethnic groups

Unaffected parents have affected children

Affected individual has unaffected children

unless they marry a heterozygote or an

affected person

Sexes are affected equally

All normal children of an affected individual will

be heterozygotes or ldquocarriersrdquo

Often there has been a consanguineous

marriage

Autosomal recessive inheritance

Autosomal Recessive

Risks to children When both parents are carriers every child they have

has a 25 chance of being affected a 50 chance to

be a carrier and a 25 to neither be affected nor a

carrier

When one parent is a carrier and the other is not a

carrier or affected every child they have has a 50

chance to be a carrier and a 50 chance to neither be a

carrier nor affected No child will be affected

When one parent is affected and the other parent is a

carrier every child they have has a 50 chance to be

affected and a 50 chance to be a carrier

When one parent is affected and the other is not a

carrier or affected every child they have will be a

carrier No child will be affected

Heterozygote Advantage in Recessive Conditions

Condition Carriers protected against

1 Thalassaemia falciparum malaria

2 Sickle cell falciparum malaria

3 (G-6-PD deficiency

falciparum malaria)

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Pedigree Analysis

Normal

Female

Normal

Male

Mating

1st born

Siblings

Affected

I

II

2 3

I

II

III

IV

2

1 2

1 2 3 4 5 6

1 2 3 4 5 6

1 2 3 4 5 6

Founders

ProbandIV - 2V

1 2

Autosomal dominant

inheritance

bull D abnormal gene

bull d normal gene

bull Each child of an

affected person has

a 50 chance of

being affected

bull Affected persons

are usually

heterozygous

Characteristics of autosomal dominant inheritance

1 A gene is dominant if it is expressed when heterozygous

2 An affected individual has a 50 chance of having an affected child

3 An affected child will have one affected parent

4 The affected parent can be either the mother or the father

5 Autosomal dominant traits have low frequencies in thepopulation

6 Autosomal dominant traits are usually lethal when homozygous

7 No skipping of generations

Autosomal Dominance

Waardenburg Syndrome

bull Hemizygous Having half the number

of alleles (eg males are hemizygous

for all X chromosome genes)

bull Expressivity The severity or intensity

of the phenotype of an allele

bull Penetrance The degree to which a

gene expresses any observable

phenotype

Pitfalls in Recognizing AD

Inheritancebull Incomplete Penetrance Some people who have the

gene mutation do not show the clinical effects

bull Penetrance Limited to one gender For example

when prostate cancer risk is inherited in an autosomal

dominant manner women who inherit the mutation are

not affected they can however pass the mutation on to

their sons

bull Variable Expressivity The gene mutation has variable

clinical manifestations the disorder may range from mild

to severe or a range of different complications may

occur among people with the mutation

Pitfalls in Recognizing AD

Inheritance

bull New Mutation An affected person may

be the first person in the family with the

condition due to a mutation arising for

the first time in sperm egg or embryo

bull Germline Mosaicism A new mutation

may arise in testis or ovary resulting in

an unaffected parent transmitting the

condition to two or more children

AD Disorders

Marfanrsquos Syndrome

Huntingtonrsquos Chorea

Osteogenesis imperfecta

Neurofibromatosis

Retinoblastoma

Tuberous sclerosis

Apertrsquos Syndrome

Multiple polyposis of colon

Achonroplacia

Brachydactylyl

Ehlers-Dalton Syndrome

Familial

Hypercholeserolemia

Porphyria

GENETIC TRAITS IN HUMANS CAN BE TRACKED

THROUGH FAMILY PEDIGREES

bull Recessive traits are often

more common in the

population than dominant

ones

bull Eg absence of freckles

more common than

presence

Polydactyly

Polydactaly

Autosomal Dominant Inheritance

Possible explanations for apparent

sporadic cases

bull Variable expressivity

bull New mutation

bull Non-penetrance

bull Gonadal mosaicism

Autosomal Recessive Carrier parents are

Heterozygotes carry the

recessive allele but exhibit

the wildtype phenotype

Normal parental phenotype

75 chance for normal

offspring

25 chance for affected

offspring

Males amp females equally

affected

ldquoInborn errors of metabolismrdquo

Associated with specific

ethnic groups

Unaffected parents have affected children

Affected individual has unaffected children

unless they marry a heterozygote or an

affected person

Sexes are affected equally

All normal children of an affected individual will

be heterozygotes or ldquocarriersrdquo

Often there has been a consanguineous

marriage

Autosomal recessive inheritance

Autosomal Recessive

Risks to children When both parents are carriers every child they have

has a 25 chance of being affected a 50 chance to

be a carrier and a 25 to neither be affected nor a

carrier

When one parent is a carrier and the other is not a

carrier or affected every child they have has a 50

chance to be a carrier and a 50 chance to neither be a

carrier nor affected No child will be affected

When one parent is affected and the other parent is a

carrier every child they have has a 50 chance to be

affected and a 50 chance to be a carrier

When one parent is affected and the other is not a

carrier or affected every child they have will be a

carrier No child will be affected

Heterozygote Advantage in Recessive Conditions

Condition Carriers protected against

1 Thalassaemia falciparum malaria

2 Sickle cell falciparum malaria

3 (G-6-PD deficiency

falciparum malaria)

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

2 3

I

II

III

IV

2

1 2

1 2 3 4 5 6

1 2 3 4 5 6

1 2 3 4 5 6

Founders

ProbandIV - 2V

1 2

Autosomal dominant

inheritance

bull D abnormal gene

bull d normal gene

bull Each child of an

affected person has

a 50 chance of

being affected

bull Affected persons

are usually

heterozygous

Characteristics of autosomal dominant inheritance

1 A gene is dominant if it is expressed when heterozygous

2 An affected individual has a 50 chance of having an affected child

3 An affected child will have one affected parent

4 The affected parent can be either the mother or the father

5 Autosomal dominant traits have low frequencies in thepopulation

6 Autosomal dominant traits are usually lethal when homozygous

7 No skipping of generations

Autosomal Dominance

Waardenburg Syndrome

bull Hemizygous Having half the number

of alleles (eg males are hemizygous

for all X chromosome genes)

bull Expressivity The severity or intensity

of the phenotype of an allele

bull Penetrance The degree to which a

gene expresses any observable

phenotype

Pitfalls in Recognizing AD

Inheritancebull Incomplete Penetrance Some people who have the

gene mutation do not show the clinical effects

bull Penetrance Limited to one gender For example

when prostate cancer risk is inherited in an autosomal

dominant manner women who inherit the mutation are

not affected they can however pass the mutation on to

their sons

bull Variable Expressivity The gene mutation has variable

clinical manifestations the disorder may range from mild

to severe or a range of different complications may

occur among people with the mutation

Pitfalls in Recognizing AD

Inheritance

bull New Mutation An affected person may

be the first person in the family with the

condition due to a mutation arising for

the first time in sperm egg or embryo

bull Germline Mosaicism A new mutation

may arise in testis or ovary resulting in

an unaffected parent transmitting the

condition to two or more children

AD Disorders

Marfanrsquos Syndrome

Huntingtonrsquos Chorea

Osteogenesis imperfecta

Neurofibromatosis

Retinoblastoma

Tuberous sclerosis

Apertrsquos Syndrome

Multiple polyposis of colon

Achonroplacia

Brachydactylyl

Ehlers-Dalton Syndrome

Familial

Hypercholeserolemia

Porphyria

GENETIC TRAITS IN HUMANS CAN BE TRACKED

THROUGH FAMILY PEDIGREES

bull Recessive traits are often

more common in the

population than dominant

ones

bull Eg absence of freckles

more common than

presence

Polydactyly

Polydactaly

Autosomal Dominant Inheritance

Possible explanations for apparent

sporadic cases

bull Variable expressivity

bull New mutation

bull Non-penetrance

bull Gonadal mosaicism

Autosomal Recessive Carrier parents are

Heterozygotes carry the

recessive allele but exhibit

the wildtype phenotype

Normal parental phenotype

75 chance for normal

offspring

25 chance for affected

offspring

Males amp females equally

affected

ldquoInborn errors of metabolismrdquo

Associated with specific

ethnic groups

Unaffected parents have affected children

Affected individual has unaffected children

unless they marry a heterozygote or an

affected person

Sexes are affected equally

All normal children of an affected individual will

be heterozygotes or ldquocarriersrdquo

Often there has been a consanguineous

marriage

Autosomal recessive inheritance

Autosomal Recessive

Risks to children When both parents are carriers every child they have

has a 25 chance of being affected a 50 chance to

be a carrier and a 25 to neither be affected nor a

carrier

When one parent is a carrier and the other is not a

carrier or affected every child they have has a 50

chance to be a carrier and a 50 chance to neither be a

carrier nor affected No child will be affected

When one parent is affected and the other parent is a

carrier every child they have has a 50 chance to be

affected and a 50 chance to be a carrier

When one parent is affected and the other is not a

carrier or affected every child they have will be a

carrier No child will be affected

Heterozygote Advantage in Recessive Conditions

Condition Carriers protected against

1 Thalassaemia falciparum malaria

2 Sickle cell falciparum malaria

3 (G-6-PD deficiency

falciparum malaria)

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Autosomal dominant

inheritance

bull D abnormal gene

bull d normal gene

bull Each child of an

affected person has

a 50 chance of

being affected

bull Affected persons

are usually

heterozygous

Characteristics of autosomal dominant inheritance

1 A gene is dominant if it is expressed when heterozygous

2 An affected individual has a 50 chance of having an affected child

3 An affected child will have one affected parent

4 The affected parent can be either the mother or the father

5 Autosomal dominant traits have low frequencies in thepopulation

6 Autosomal dominant traits are usually lethal when homozygous

7 No skipping of generations

Autosomal Dominance

Waardenburg Syndrome

bull Hemizygous Having half the number

of alleles (eg males are hemizygous

for all X chromosome genes)

bull Expressivity The severity or intensity

of the phenotype of an allele

bull Penetrance The degree to which a

gene expresses any observable

phenotype

Pitfalls in Recognizing AD

Inheritancebull Incomplete Penetrance Some people who have the

gene mutation do not show the clinical effects

bull Penetrance Limited to one gender For example

when prostate cancer risk is inherited in an autosomal

dominant manner women who inherit the mutation are

not affected they can however pass the mutation on to

their sons

bull Variable Expressivity The gene mutation has variable

clinical manifestations the disorder may range from mild

to severe or a range of different complications may

occur among people with the mutation

Pitfalls in Recognizing AD

Inheritance

bull New Mutation An affected person may

be the first person in the family with the

condition due to a mutation arising for

the first time in sperm egg or embryo

bull Germline Mosaicism A new mutation

may arise in testis or ovary resulting in

an unaffected parent transmitting the

condition to two or more children

AD Disorders

Marfanrsquos Syndrome

Huntingtonrsquos Chorea

Osteogenesis imperfecta

Neurofibromatosis

Retinoblastoma

Tuberous sclerosis

Apertrsquos Syndrome

Multiple polyposis of colon

Achonroplacia

Brachydactylyl

Ehlers-Dalton Syndrome

Familial

Hypercholeserolemia

Porphyria

GENETIC TRAITS IN HUMANS CAN BE TRACKED

THROUGH FAMILY PEDIGREES

bull Recessive traits are often

more common in the

population than dominant

ones

bull Eg absence of freckles

more common than

presence

Polydactyly

Polydactaly

Autosomal Dominant Inheritance

Possible explanations for apparent

sporadic cases

bull Variable expressivity

bull New mutation

bull Non-penetrance

bull Gonadal mosaicism

Autosomal Recessive Carrier parents are

Heterozygotes carry the

recessive allele but exhibit

the wildtype phenotype

Normal parental phenotype

75 chance for normal

offspring

25 chance for affected

offspring

Males amp females equally

affected

ldquoInborn errors of metabolismrdquo

Associated with specific

ethnic groups

Unaffected parents have affected children

Affected individual has unaffected children

unless they marry a heterozygote or an

affected person

Sexes are affected equally

All normal children of an affected individual will

be heterozygotes or ldquocarriersrdquo

Often there has been a consanguineous

marriage

Autosomal recessive inheritance

Autosomal Recessive

Risks to children When both parents are carriers every child they have

has a 25 chance of being affected a 50 chance to

be a carrier and a 25 to neither be affected nor a

carrier

When one parent is a carrier and the other is not a

carrier or affected every child they have has a 50

chance to be a carrier and a 50 chance to neither be a

carrier nor affected No child will be affected

When one parent is affected and the other parent is a

carrier every child they have has a 50 chance to be

affected and a 50 chance to be a carrier

When one parent is affected and the other is not a

carrier or affected every child they have will be a

carrier No child will be affected

Heterozygote Advantage in Recessive Conditions

Condition Carriers protected against

1 Thalassaemia falciparum malaria

2 Sickle cell falciparum malaria

3 (G-6-PD deficiency

falciparum malaria)

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Characteristics of autosomal dominant inheritance

1 A gene is dominant if it is expressed when heterozygous

2 An affected individual has a 50 chance of having an affected child

3 An affected child will have one affected parent

4 The affected parent can be either the mother or the father

5 Autosomal dominant traits have low frequencies in thepopulation

6 Autosomal dominant traits are usually lethal when homozygous

7 No skipping of generations

Autosomal Dominance

Waardenburg Syndrome

bull Hemizygous Having half the number

of alleles (eg males are hemizygous

for all X chromosome genes)

bull Expressivity The severity or intensity

of the phenotype of an allele

bull Penetrance The degree to which a

gene expresses any observable

phenotype

Pitfalls in Recognizing AD

Inheritancebull Incomplete Penetrance Some people who have the

gene mutation do not show the clinical effects

bull Penetrance Limited to one gender For example

when prostate cancer risk is inherited in an autosomal

dominant manner women who inherit the mutation are

not affected they can however pass the mutation on to

their sons

bull Variable Expressivity The gene mutation has variable

clinical manifestations the disorder may range from mild

to severe or a range of different complications may

occur among people with the mutation

Pitfalls in Recognizing AD

Inheritance

bull New Mutation An affected person may

be the first person in the family with the

condition due to a mutation arising for

the first time in sperm egg or embryo

bull Germline Mosaicism A new mutation

may arise in testis or ovary resulting in

an unaffected parent transmitting the

condition to two or more children

AD Disorders

Marfanrsquos Syndrome

Huntingtonrsquos Chorea

Osteogenesis imperfecta

Neurofibromatosis

Retinoblastoma

Tuberous sclerosis

Apertrsquos Syndrome

Multiple polyposis of colon

Achonroplacia

Brachydactylyl

Ehlers-Dalton Syndrome

Familial

Hypercholeserolemia

Porphyria

GENETIC TRAITS IN HUMANS CAN BE TRACKED

THROUGH FAMILY PEDIGREES

bull Recessive traits are often

more common in the

population than dominant

ones

bull Eg absence of freckles

more common than

presence

Polydactyly

Polydactaly

Autosomal Dominant Inheritance

Possible explanations for apparent

sporadic cases

bull Variable expressivity

bull New mutation

bull Non-penetrance

bull Gonadal mosaicism

Autosomal Recessive Carrier parents are

Heterozygotes carry the

recessive allele but exhibit

the wildtype phenotype

Normal parental phenotype

75 chance for normal

offspring

25 chance for affected

offspring

Males amp females equally

affected

ldquoInborn errors of metabolismrdquo

Associated with specific

ethnic groups

Unaffected parents have affected children

Affected individual has unaffected children

unless they marry a heterozygote or an

affected person

Sexes are affected equally

All normal children of an affected individual will

be heterozygotes or ldquocarriersrdquo

Often there has been a consanguineous

marriage

Autosomal recessive inheritance

Autosomal Recessive

Risks to children When both parents are carriers every child they have

has a 25 chance of being affected a 50 chance to

be a carrier and a 25 to neither be affected nor a

carrier

When one parent is a carrier and the other is not a

carrier or affected every child they have has a 50

chance to be a carrier and a 50 chance to neither be a

carrier nor affected No child will be affected

When one parent is affected and the other parent is a

carrier every child they have has a 50 chance to be

affected and a 50 chance to be a carrier

When one parent is affected and the other is not a

carrier or affected every child they have will be a

carrier No child will be affected

Heterozygote Advantage in Recessive Conditions

Condition Carriers protected against

1 Thalassaemia falciparum malaria

2 Sickle cell falciparum malaria

3 (G-6-PD deficiency

falciparum malaria)

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Autosomal Dominance

Waardenburg Syndrome

bull Hemizygous Having half the number

of alleles (eg males are hemizygous

for all X chromosome genes)

bull Expressivity The severity or intensity

of the phenotype of an allele

bull Penetrance The degree to which a

gene expresses any observable

phenotype

Pitfalls in Recognizing AD

Inheritancebull Incomplete Penetrance Some people who have the

gene mutation do not show the clinical effects

bull Penetrance Limited to one gender For example

when prostate cancer risk is inherited in an autosomal

dominant manner women who inherit the mutation are

not affected they can however pass the mutation on to

their sons

bull Variable Expressivity The gene mutation has variable

clinical manifestations the disorder may range from mild

to severe or a range of different complications may

occur among people with the mutation

Pitfalls in Recognizing AD

Inheritance

bull New Mutation An affected person may

be the first person in the family with the

condition due to a mutation arising for

the first time in sperm egg or embryo

bull Germline Mosaicism A new mutation

may arise in testis or ovary resulting in

an unaffected parent transmitting the

condition to two or more children

AD Disorders

Marfanrsquos Syndrome

Huntingtonrsquos Chorea

Osteogenesis imperfecta

Neurofibromatosis

Retinoblastoma

Tuberous sclerosis

Apertrsquos Syndrome

Multiple polyposis of colon

Achonroplacia

Brachydactylyl

Ehlers-Dalton Syndrome

Familial

Hypercholeserolemia

Porphyria

GENETIC TRAITS IN HUMANS CAN BE TRACKED

THROUGH FAMILY PEDIGREES

bull Recessive traits are often

more common in the

population than dominant

ones

bull Eg absence of freckles

more common than

presence

Polydactyly

Polydactaly

Autosomal Dominant Inheritance

Possible explanations for apparent

sporadic cases

bull Variable expressivity

bull New mutation

bull Non-penetrance

bull Gonadal mosaicism

Autosomal Recessive Carrier parents are

Heterozygotes carry the

recessive allele but exhibit

the wildtype phenotype

Normal parental phenotype

75 chance for normal

offspring

25 chance for affected

offspring

Males amp females equally

affected

ldquoInborn errors of metabolismrdquo

Associated with specific

ethnic groups

Unaffected parents have affected children

Affected individual has unaffected children

unless they marry a heterozygote or an

affected person

Sexes are affected equally

All normal children of an affected individual will

be heterozygotes or ldquocarriersrdquo

Often there has been a consanguineous

marriage

Autosomal recessive inheritance

Autosomal Recessive

Risks to children When both parents are carriers every child they have

has a 25 chance of being affected a 50 chance to

be a carrier and a 25 to neither be affected nor a

carrier

When one parent is a carrier and the other is not a

carrier or affected every child they have has a 50

chance to be a carrier and a 50 chance to neither be a

carrier nor affected No child will be affected

When one parent is affected and the other parent is a

carrier every child they have has a 50 chance to be

affected and a 50 chance to be a carrier

When one parent is affected and the other is not a

carrier or affected every child they have will be a

carrier No child will be affected

Heterozygote Advantage in Recessive Conditions

Condition Carriers protected against

1 Thalassaemia falciparum malaria

2 Sickle cell falciparum malaria

3 (G-6-PD deficiency

falciparum malaria)

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

bull Hemizygous Having half the number

of alleles (eg males are hemizygous

for all X chromosome genes)

bull Expressivity The severity or intensity

of the phenotype of an allele

bull Penetrance The degree to which a

gene expresses any observable

phenotype

Pitfalls in Recognizing AD

Inheritancebull Incomplete Penetrance Some people who have the

gene mutation do not show the clinical effects

bull Penetrance Limited to one gender For example

when prostate cancer risk is inherited in an autosomal

dominant manner women who inherit the mutation are

not affected they can however pass the mutation on to

their sons

bull Variable Expressivity The gene mutation has variable

clinical manifestations the disorder may range from mild

to severe or a range of different complications may

occur among people with the mutation

Pitfalls in Recognizing AD

Inheritance

bull New Mutation An affected person may

be the first person in the family with the

condition due to a mutation arising for

the first time in sperm egg or embryo

bull Germline Mosaicism A new mutation

may arise in testis or ovary resulting in

an unaffected parent transmitting the

condition to two or more children

AD Disorders

Marfanrsquos Syndrome

Huntingtonrsquos Chorea

Osteogenesis imperfecta

Neurofibromatosis

Retinoblastoma

Tuberous sclerosis

Apertrsquos Syndrome

Multiple polyposis of colon

Achonroplacia

Brachydactylyl

Ehlers-Dalton Syndrome

Familial

Hypercholeserolemia

Porphyria

GENETIC TRAITS IN HUMANS CAN BE TRACKED

THROUGH FAMILY PEDIGREES

bull Recessive traits are often

more common in the

population than dominant

ones

bull Eg absence of freckles

more common than

presence

Polydactyly

Polydactaly

Autosomal Dominant Inheritance

Possible explanations for apparent

sporadic cases

bull Variable expressivity

bull New mutation

bull Non-penetrance

bull Gonadal mosaicism

Autosomal Recessive Carrier parents are

Heterozygotes carry the

recessive allele but exhibit

the wildtype phenotype

Normal parental phenotype

75 chance for normal

offspring

25 chance for affected

offspring

Males amp females equally

affected

ldquoInborn errors of metabolismrdquo

Associated with specific

ethnic groups

Unaffected parents have affected children

Affected individual has unaffected children

unless they marry a heterozygote or an

affected person

Sexes are affected equally

All normal children of an affected individual will

be heterozygotes or ldquocarriersrdquo

Often there has been a consanguineous

marriage

Autosomal recessive inheritance

Autosomal Recessive

Risks to children When both parents are carriers every child they have

has a 25 chance of being affected a 50 chance to

be a carrier and a 25 to neither be affected nor a

carrier

When one parent is a carrier and the other is not a

carrier or affected every child they have has a 50

chance to be a carrier and a 50 chance to neither be a

carrier nor affected No child will be affected

When one parent is affected and the other parent is a

carrier every child they have has a 50 chance to be

affected and a 50 chance to be a carrier

When one parent is affected and the other is not a

carrier or affected every child they have will be a

carrier No child will be affected

Heterozygote Advantage in Recessive Conditions

Condition Carriers protected against

1 Thalassaemia falciparum malaria

2 Sickle cell falciparum malaria

3 (G-6-PD deficiency

falciparum malaria)

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Pitfalls in Recognizing AD

Inheritancebull Incomplete Penetrance Some people who have the

gene mutation do not show the clinical effects

bull Penetrance Limited to one gender For example

when prostate cancer risk is inherited in an autosomal

dominant manner women who inherit the mutation are

not affected they can however pass the mutation on to

their sons

bull Variable Expressivity The gene mutation has variable

clinical manifestations the disorder may range from mild

to severe or a range of different complications may

occur among people with the mutation

Pitfalls in Recognizing AD

Inheritance

bull New Mutation An affected person may

be the first person in the family with the

condition due to a mutation arising for

the first time in sperm egg or embryo

bull Germline Mosaicism A new mutation

may arise in testis or ovary resulting in

an unaffected parent transmitting the

condition to two or more children

AD Disorders

Marfanrsquos Syndrome

Huntingtonrsquos Chorea

Osteogenesis imperfecta

Neurofibromatosis

Retinoblastoma

Tuberous sclerosis

Apertrsquos Syndrome

Multiple polyposis of colon

Achonroplacia

Brachydactylyl

Ehlers-Dalton Syndrome

Familial

Hypercholeserolemia

Porphyria

GENETIC TRAITS IN HUMANS CAN BE TRACKED

THROUGH FAMILY PEDIGREES

bull Recessive traits are often

more common in the

population than dominant

ones

bull Eg absence of freckles

more common than

presence

Polydactyly

Polydactaly

Autosomal Dominant Inheritance

Possible explanations for apparent

sporadic cases

bull Variable expressivity

bull New mutation

bull Non-penetrance

bull Gonadal mosaicism

Autosomal Recessive Carrier parents are

Heterozygotes carry the

recessive allele but exhibit

the wildtype phenotype

Normal parental phenotype

75 chance for normal

offspring

25 chance for affected

offspring

Males amp females equally

affected

ldquoInborn errors of metabolismrdquo

Associated with specific

ethnic groups

Unaffected parents have affected children

Affected individual has unaffected children

unless they marry a heterozygote or an

affected person

Sexes are affected equally

All normal children of an affected individual will

be heterozygotes or ldquocarriersrdquo

Often there has been a consanguineous

marriage

Autosomal recessive inheritance

Autosomal Recessive

Risks to children When both parents are carriers every child they have

has a 25 chance of being affected a 50 chance to

be a carrier and a 25 to neither be affected nor a

carrier

When one parent is a carrier and the other is not a

carrier or affected every child they have has a 50

chance to be a carrier and a 50 chance to neither be a

carrier nor affected No child will be affected

When one parent is affected and the other parent is a

carrier every child they have has a 50 chance to be

affected and a 50 chance to be a carrier

When one parent is affected and the other is not a

carrier or affected every child they have will be a

carrier No child will be affected

Heterozygote Advantage in Recessive Conditions

Condition Carriers protected against

1 Thalassaemia falciparum malaria

2 Sickle cell falciparum malaria

3 (G-6-PD deficiency

falciparum malaria)

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Pitfalls in Recognizing AD

Inheritance

bull New Mutation An affected person may

be the first person in the family with the

condition due to a mutation arising for

the first time in sperm egg or embryo

bull Germline Mosaicism A new mutation

may arise in testis or ovary resulting in

an unaffected parent transmitting the

condition to two or more children

AD Disorders

Marfanrsquos Syndrome

Huntingtonrsquos Chorea

Osteogenesis imperfecta

Neurofibromatosis

Retinoblastoma

Tuberous sclerosis

Apertrsquos Syndrome

Multiple polyposis of colon

Achonroplacia

Brachydactylyl

Ehlers-Dalton Syndrome

Familial

Hypercholeserolemia

Porphyria

GENETIC TRAITS IN HUMANS CAN BE TRACKED

THROUGH FAMILY PEDIGREES

bull Recessive traits are often

more common in the

population than dominant

ones

bull Eg absence of freckles

more common than

presence

Polydactyly

Polydactaly

Autosomal Dominant Inheritance

Possible explanations for apparent

sporadic cases

bull Variable expressivity

bull New mutation

bull Non-penetrance

bull Gonadal mosaicism

Autosomal Recessive Carrier parents are

Heterozygotes carry the

recessive allele but exhibit

the wildtype phenotype

Normal parental phenotype

75 chance for normal

offspring

25 chance for affected

offspring

Males amp females equally

affected

ldquoInborn errors of metabolismrdquo

Associated with specific

ethnic groups

Unaffected parents have affected children

Affected individual has unaffected children

unless they marry a heterozygote or an

affected person

Sexes are affected equally

All normal children of an affected individual will

be heterozygotes or ldquocarriersrdquo

Often there has been a consanguineous

marriage

Autosomal recessive inheritance

Autosomal Recessive

Risks to children When both parents are carriers every child they have

has a 25 chance of being affected a 50 chance to

be a carrier and a 25 to neither be affected nor a

carrier

When one parent is a carrier and the other is not a

carrier or affected every child they have has a 50

chance to be a carrier and a 50 chance to neither be a

carrier nor affected No child will be affected

When one parent is affected and the other parent is a

carrier every child they have has a 50 chance to be

affected and a 50 chance to be a carrier

When one parent is affected and the other is not a

carrier or affected every child they have will be a

carrier No child will be affected

Heterozygote Advantage in Recessive Conditions

Condition Carriers protected against

1 Thalassaemia falciparum malaria

2 Sickle cell falciparum malaria

3 (G-6-PD deficiency

falciparum malaria)

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

AD Disorders

Marfanrsquos Syndrome

Huntingtonrsquos Chorea

Osteogenesis imperfecta

Neurofibromatosis

Retinoblastoma

Tuberous sclerosis

Apertrsquos Syndrome

Multiple polyposis of colon

Achonroplacia

Brachydactylyl

Ehlers-Dalton Syndrome

Familial

Hypercholeserolemia

Porphyria

GENETIC TRAITS IN HUMANS CAN BE TRACKED

THROUGH FAMILY PEDIGREES

bull Recessive traits are often

more common in the

population than dominant

ones

bull Eg absence of freckles

more common than

presence

Polydactyly

Polydactaly

Autosomal Dominant Inheritance

Possible explanations for apparent

sporadic cases

bull Variable expressivity

bull New mutation

bull Non-penetrance

bull Gonadal mosaicism

Autosomal Recessive Carrier parents are

Heterozygotes carry the

recessive allele but exhibit

the wildtype phenotype

Normal parental phenotype

75 chance for normal

offspring

25 chance for affected

offspring

Males amp females equally

affected

ldquoInborn errors of metabolismrdquo

Associated with specific

ethnic groups

Unaffected parents have affected children

Affected individual has unaffected children

unless they marry a heterozygote or an

affected person

Sexes are affected equally

All normal children of an affected individual will

be heterozygotes or ldquocarriersrdquo

Often there has been a consanguineous

marriage

Autosomal recessive inheritance

Autosomal Recessive

Risks to children When both parents are carriers every child they have

has a 25 chance of being affected a 50 chance to

be a carrier and a 25 to neither be affected nor a

carrier

When one parent is a carrier and the other is not a

carrier or affected every child they have has a 50

chance to be a carrier and a 50 chance to neither be a

carrier nor affected No child will be affected

When one parent is affected and the other parent is a

carrier every child they have has a 50 chance to be

affected and a 50 chance to be a carrier

When one parent is affected and the other is not a

carrier or affected every child they have will be a

carrier No child will be affected

Heterozygote Advantage in Recessive Conditions

Condition Carriers protected against

1 Thalassaemia falciparum malaria

2 Sickle cell falciparum malaria

3 (G-6-PD deficiency

falciparum malaria)

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

GENETIC TRAITS IN HUMANS CAN BE TRACKED

THROUGH FAMILY PEDIGREES

bull Recessive traits are often

more common in the

population than dominant

ones

bull Eg absence of freckles

more common than

presence

Polydactyly

Polydactaly

Autosomal Dominant Inheritance

Possible explanations for apparent

sporadic cases

bull Variable expressivity

bull New mutation

bull Non-penetrance

bull Gonadal mosaicism

Autosomal Recessive Carrier parents are

Heterozygotes carry the

recessive allele but exhibit

the wildtype phenotype

Normal parental phenotype

75 chance for normal

offspring

25 chance for affected

offspring

Males amp females equally

affected

ldquoInborn errors of metabolismrdquo

Associated with specific

ethnic groups

Unaffected parents have affected children

Affected individual has unaffected children

unless they marry a heterozygote or an

affected person

Sexes are affected equally

All normal children of an affected individual will

be heterozygotes or ldquocarriersrdquo

Often there has been a consanguineous

marriage

Autosomal recessive inheritance

Autosomal Recessive

Risks to children When both parents are carriers every child they have

has a 25 chance of being affected a 50 chance to

be a carrier and a 25 to neither be affected nor a

carrier

When one parent is a carrier and the other is not a

carrier or affected every child they have has a 50

chance to be a carrier and a 50 chance to neither be a

carrier nor affected No child will be affected

When one parent is affected and the other parent is a

carrier every child they have has a 50 chance to be

affected and a 50 chance to be a carrier

When one parent is affected and the other is not a

carrier or affected every child they have will be a

carrier No child will be affected

Heterozygote Advantage in Recessive Conditions

Condition Carriers protected against

1 Thalassaemia falciparum malaria

2 Sickle cell falciparum malaria

3 (G-6-PD deficiency

falciparum malaria)

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Polydactyly

Polydactaly

Autosomal Dominant Inheritance

Possible explanations for apparent

sporadic cases

bull Variable expressivity

bull New mutation

bull Non-penetrance

bull Gonadal mosaicism

Autosomal Recessive Carrier parents are

Heterozygotes carry the

recessive allele but exhibit

the wildtype phenotype

Normal parental phenotype

75 chance for normal

offspring

25 chance for affected

offspring

Males amp females equally

affected

ldquoInborn errors of metabolismrdquo

Associated with specific

ethnic groups

Unaffected parents have affected children

Affected individual has unaffected children

unless they marry a heterozygote or an

affected person

Sexes are affected equally

All normal children of an affected individual will

be heterozygotes or ldquocarriersrdquo

Often there has been a consanguineous

marriage

Autosomal recessive inheritance

Autosomal Recessive

Risks to children When both parents are carriers every child they have

has a 25 chance of being affected a 50 chance to

be a carrier and a 25 to neither be affected nor a

carrier

When one parent is a carrier and the other is not a

carrier or affected every child they have has a 50

chance to be a carrier and a 50 chance to neither be a

carrier nor affected No child will be affected

When one parent is affected and the other parent is a

carrier every child they have has a 50 chance to be

affected and a 50 chance to be a carrier

When one parent is affected and the other is not a

carrier or affected every child they have will be a

carrier No child will be affected

Heterozygote Advantage in Recessive Conditions

Condition Carriers protected against

1 Thalassaemia falciparum malaria

2 Sickle cell falciparum malaria

3 (G-6-PD deficiency

falciparum malaria)

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Polydactaly

Autosomal Dominant Inheritance

Possible explanations for apparent

sporadic cases

bull Variable expressivity

bull New mutation

bull Non-penetrance

bull Gonadal mosaicism

Autosomal Recessive Carrier parents are

Heterozygotes carry the

recessive allele but exhibit

the wildtype phenotype

Normal parental phenotype

75 chance for normal

offspring

25 chance for affected

offspring

Males amp females equally

affected

ldquoInborn errors of metabolismrdquo

Associated with specific

ethnic groups

Unaffected parents have affected children

Affected individual has unaffected children

unless they marry a heterozygote or an

affected person

Sexes are affected equally

All normal children of an affected individual will

be heterozygotes or ldquocarriersrdquo

Often there has been a consanguineous

marriage

Autosomal recessive inheritance

Autosomal Recessive

Risks to children When both parents are carriers every child they have

has a 25 chance of being affected a 50 chance to

be a carrier and a 25 to neither be affected nor a

carrier

When one parent is a carrier and the other is not a

carrier or affected every child they have has a 50

chance to be a carrier and a 50 chance to neither be a

carrier nor affected No child will be affected

When one parent is affected and the other parent is a

carrier every child they have has a 50 chance to be

affected and a 50 chance to be a carrier

When one parent is affected and the other is not a

carrier or affected every child they have will be a

carrier No child will be affected

Heterozygote Advantage in Recessive Conditions

Condition Carriers protected against

1 Thalassaemia falciparum malaria

2 Sickle cell falciparum malaria

3 (G-6-PD deficiency

falciparum malaria)

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Possible explanations for apparent

sporadic cases

bull Variable expressivity

bull New mutation

bull Non-penetrance

bull Gonadal mosaicism

Autosomal Recessive Carrier parents are

Heterozygotes carry the

recessive allele but exhibit

the wildtype phenotype

Normal parental phenotype

75 chance for normal

offspring

25 chance for affected

offspring

Males amp females equally

affected

ldquoInborn errors of metabolismrdquo

Associated with specific

ethnic groups

Unaffected parents have affected children

Affected individual has unaffected children

unless they marry a heterozygote or an

affected person

Sexes are affected equally

All normal children of an affected individual will

be heterozygotes or ldquocarriersrdquo

Often there has been a consanguineous

marriage

Autosomal recessive inheritance

Autosomal Recessive

Risks to children When both parents are carriers every child they have

has a 25 chance of being affected a 50 chance to

be a carrier and a 25 to neither be affected nor a

carrier

When one parent is a carrier and the other is not a

carrier or affected every child they have has a 50

chance to be a carrier and a 50 chance to neither be a

carrier nor affected No child will be affected

When one parent is affected and the other parent is a

carrier every child they have has a 50 chance to be

affected and a 50 chance to be a carrier

When one parent is affected and the other is not a

carrier or affected every child they have will be a

carrier No child will be affected

Heterozygote Advantage in Recessive Conditions

Condition Carriers protected against

1 Thalassaemia falciparum malaria

2 Sickle cell falciparum malaria

3 (G-6-PD deficiency

falciparum malaria)

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Autosomal Recessive Carrier parents are

Heterozygotes carry the

recessive allele but exhibit

the wildtype phenotype

Normal parental phenotype

75 chance for normal

offspring

25 chance for affected

offspring

Males amp females equally

affected

ldquoInborn errors of metabolismrdquo

Associated with specific

ethnic groups

Unaffected parents have affected children

Affected individual has unaffected children

unless they marry a heterozygote or an

affected person

Sexes are affected equally

All normal children of an affected individual will

be heterozygotes or ldquocarriersrdquo

Often there has been a consanguineous

marriage

Autosomal recessive inheritance

Autosomal Recessive

Risks to children When both parents are carriers every child they have

has a 25 chance of being affected a 50 chance to

be a carrier and a 25 to neither be affected nor a

carrier

When one parent is a carrier and the other is not a

carrier or affected every child they have has a 50

chance to be a carrier and a 50 chance to neither be a

carrier nor affected No child will be affected

When one parent is affected and the other parent is a

carrier every child they have has a 50 chance to be

affected and a 50 chance to be a carrier

When one parent is affected and the other is not a

carrier or affected every child they have will be a

carrier No child will be affected

Heterozygote Advantage in Recessive Conditions

Condition Carriers protected against

1 Thalassaemia falciparum malaria

2 Sickle cell falciparum malaria

3 (G-6-PD deficiency

falciparum malaria)

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Unaffected parents have affected children

Affected individual has unaffected children

unless they marry a heterozygote or an

affected person

Sexes are affected equally

All normal children of an affected individual will

be heterozygotes or ldquocarriersrdquo

Often there has been a consanguineous

marriage

Autosomal recessive inheritance

Autosomal Recessive

Risks to children When both parents are carriers every child they have

has a 25 chance of being affected a 50 chance to

be a carrier and a 25 to neither be affected nor a

carrier

When one parent is a carrier and the other is not a

carrier or affected every child they have has a 50

chance to be a carrier and a 50 chance to neither be a

carrier nor affected No child will be affected

When one parent is affected and the other parent is a

carrier every child they have has a 50 chance to be

affected and a 50 chance to be a carrier

When one parent is affected and the other is not a

carrier or affected every child they have will be a

carrier No child will be affected

Heterozygote Advantage in Recessive Conditions

Condition Carriers protected against

1 Thalassaemia falciparum malaria

2 Sickle cell falciparum malaria

3 (G-6-PD deficiency

falciparum malaria)

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Autosomal Recessive

Risks to children When both parents are carriers every child they have

has a 25 chance of being affected a 50 chance to

be a carrier and a 25 to neither be affected nor a

carrier

When one parent is a carrier and the other is not a

carrier or affected every child they have has a 50

chance to be a carrier and a 50 chance to neither be a

carrier nor affected No child will be affected

When one parent is affected and the other parent is a

carrier every child they have has a 50 chance to be

affected and a 50 chance to be a carrier

When one parent is affected and the other is not a

carrier or affected every child they have will be a

carrier No child will be affected

Heterozygote Advantage in Recessive Conditions

Condition Carriers protected against

1 Thalassaemia falciparum malaria

2 Sickle cell falciparum malaria

3 (G-6-PD deficiency

falciparum malaria)

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Risks to children When both parents are carriers every child they have

has a 25 chance of being affected a 50 chance to

be a carrier and a 25 to neither be affected nor a

carrier

When one parent is a carrier and the other is not a

carrier or affected every child they have has a 50

chance to be a carrier and a 50 chance to neither be a

carrier nor affected No child will be affected

When one parent is affected and the other parent is a

carrier every child they have has a 50 chance to be

affected and a 50 chance to be a carrier

When one parent is affected and the other is not a

carrier or affected every child they have will be a

carrier No child will be affected

Heterozygote Advantage in Recessive Conditions

Condition Carriers protected against

1 Thalassaemia falciparum malaria

2 Sickle cell falciparum malaria

3 (G-6-PD deficiency

falciparum malaria)

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Heterozygote Advantage in Recessive Conditions

Condition Carriers protected against

1 Thalassaemia falciparum malaria

2 Sickle cell falciparum malaria

3 (G-6-PD deficiency

falciparum malaria)

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Examples of AR conditions

bull Beta thalassemia

bull Sickle cell anemia

bull Congenital adrenal hyperplasia

bull Familial Mediterranean fever

bull Cystic fibrosis

bull Phenylketonuria

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Dominant Versus Recessive

1 Achnondroplassia

Homozygote ndash Reduced Stature Usually Die in Infancy Heterozygote

- Usually normal life

2 Familial Isolated Growth Hormone Deficiency (IGHD)

Several mutations on Ch 17 (GH1)

RECESSIVE Nonsense Mutation

1 Heterozygote Produce sufficient GH ndash Normal

2 Homozygote No GH production ndash Affected

DOMINANT Splicing Site mutation at exon 3 Mutated GH produce

Disulfide bond with the normal GH produced by normal gene

3 Sickle Cell Anemia

Normal Altitude ndash Trait is living normal Recessive

High Altitude - Trait is Affected Dominant

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Factors that may complicate

Inheritance Patterns

bull Codominance

bull Epistasis

bull New mutation

bull Germline Mosaicism

bull Delayed age of onset

bull Reduced penetrance

bull Variable expression

bull Pleiotropy and Heterogeneity

bull Genomic Imprinting

bull Anticipation

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Codominance

bull Both traits are expressed

ndash the phenotype shows

the separate traits of

both alleles

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

ceramide

fucose

N-acetylglucosamine (GlcNAc)

galactose

A-transferase

N-acetylgalactosamine (GalNAc) transferase

galactose

B-transferase

Galactose transferase

A

BH (type O)

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Epistasis

bull hh genotype = no H protein

All ABO genotypes appear

as type O

When one gene affects the expression of a second gene

H gene is epistatic to the ABO gene

bull H protein attaches the A or B protein to the cell surface

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

More gene

interactionshellip

Epistasis - when one gene alters the phenotypic expression of another gene

The C gene determines whether or not pigment is deposited

The B gene determines what color the pigment will be No

pigment

Pigmented

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

New Mutation

bull New mutations are frequent

cause of the appearance of a

genetic disease in an

individual with no previous

family history of the disorder

bull The recurrence risk for the

individualrsquos sibling is very

low but it may be

substantially elevated for the

individualrsquos offspringExample

Achnondroplasia = 78 are new mutations 18 inherited

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Germline Mosaicism

bull Definitions

ndash Mosaicism is an individual who has

more than one genetically distinct

cell lines in his or her body

ndash Germline Mosaicism Occurs when

all or part of a parentrsquos germline is

affected by a disease mutation But

somatic cells are NOT affected

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Germ line Mosaicism

bull Suspicion When two or more offspring

presented with an AD disease when

there is no family history of disease

bull Reason Because mutation is rare

event it is unlikely that this would be

due to multiple mutations in the same

family

bull Occurance Elevates recurrence risk

for future offspring of mosaic parent

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Germline Mosaicism m

Examples

bull Osteogenesis Imperfecta ndash

OI type II lethal perinatal form

bull Achondroplasia

bull Duchennes Muscular Dystrophy

bull Hemophilia A

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Delayed Age of Onset

bull Can cause difficulty in deducing mode of

inheritance

bull Not possible until later in life to

determine whether an individual is

carrier for a mutation

bull Some examples include ndash Huntington Disease

ndash Polycystic kidney disease

ndash Hemochromatosis

ndash Familial Alzheimer disease

ndash AD form of breast cancer

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

AnticipationMyotonic dystrophy

Number of CTG repeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2000 or more severely affected

bull No of repeats often increases with succeeding

generations

bull Severe congenital form occurs only when disease

gene is inherited from mother

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Trinucleotide Repeat

Expansions

Huntington - CAG

Myotonic dystrophy - CTG

x-linked spinal and bulbar muscular atrophy -

CAG

Spinocerebellar ataxia type I - CAG

Fragile X syndrome (FRAXA) - CGG

Fragile site FRAXE - CGG

Machado-Joseph diseas - CAG

Friedreichrsquos ataxia - GAA

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

REDUCED PENETRANCE

Diseases genes in which an individual

may have the disease genotype without

expressing of the disease

Phenotype

bull Retinoplastoma AD malignant eye tumor

is a good example of reduced penetrance

bull 10 of gene carriers do not show the

disease = OBLIGATE CARRIERS Penetrance

= 90

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Variable Expression

Penetrance may be complete but severity of disease can vary greatly

Well-studied example is neurofibromatosis type 1 Parent with mild expression of disease (so mild they may not know they carry gene) can transmit gene to child who can have severe expression

Provides a mechanism for disease genes to survive at higher frequencies in populations

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Variable Expression - Causes

bull Environmental factors

in absence of environmental factor

gene is expressed with diminished

severity or not at all

bull Modifier genes

ndash interaction of other genes

bull Allelic heterogeneity

b - globin mutations that can cause

sickle cell disease or various b - thal

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Variable Expressivity

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Pleiotropy

bull The appearance of several apparently unrelated phenotypic effects caused by a single gene

bull Refers to a Mendelian disorder with several symptoms

bull Different subset of symptoms in different individuals

bull Usually means that a genes is involved in multiple processes

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

PLEIOTROPY

bull Marfan Syndrome AD fibrillin - chromosome

15q Affects Eye Skeleton and Cardiovascular

systems

bull CF AR Affects the Sweat glands Lungs

and Pancrease

bull OI AD Affects the Bones Teeth and

Sclera

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Genetic heterogeneity

Individuals with identical phenotypes may reflect

different genetic causes

bull Deafness

bull Albinism

bull Cleft palate

bull Poor blood clotting

Different genes can produce identical phenotypes

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

HETEROGENEITYA disease that can be caused by mutations at a different loci in different families

Disease Description Chromosomes on which

known loci is located

bull Retinitis pigmentosa Progressive retinopathy and gt 20 chromosome regions

loss of vision identified

bull Osteogenesis imperfecta Brittle bone disease 7 17

bull Charcot-Maric-Tooth diseas Peripheral neuropathy 1 5 8 11 17 X

bullbull Familial Alzheimer disease Progressive dementia 1 14 19 21

bull Familial melanoma Autosomal dominant melanoma 1 9

(skin cancer)

bull Hereditary nonpolyposis Autosomal dominant colorectal Ca 2p 2q 3 7

colorectal cancer

bull Autosomal dominant breast Predisposition to early-onset breast and 1317

cancer ovarian cancer (chromosome 17 form)

bull Tuberous sclerosis Seizures facial angiofibromas hypopig- 916

mented macules mental retardation

bull Adult polycystic kidney Accumulation of renal cysts leading to 416

disease kidney failure

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

VARIABLE EXPRESSION

Penetrance is complete but severity of the disease is variable

bull Environmental effects

bull Modifier genes

bull Different expression in different families

bull Allelic heterogeneity- b-Thal Sickle Cell

bull Osteogenesis imperfecta Mutations at COOH terminal more sever than NH2

terminal

Accidental fracture Complications

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

DELAYED AGE OF ONSET

Observed in many genetic diseases It

complicate the interpretation of

inheritance patterns in the families

Huntington Disease ndash AD

Hemochromatosis ndash AR FATAL

Familial Alzheimer Disease

Familial Breast Cancer

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Genomic Imprintingbull Genes inherited from the mother while

having the same DNA sequence differ in

some other way from those of the father

(the ldquoimprintrdquo)

bull The imprint alters the activity level of

genes so del of paternally or maternally

derived chromosomes may produce

different phenotypes

bull ldquoParental origin effectsrdquo - Methylation - the

more methylated a gene is the less likely it

is to be transcribed into mRNA

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

GENETIC IMPRINTINGbull Some disease gene may be expressed differently when

inherited from one sex versus other

bull It is associated with and possibly caused by methylation of DNA

Interstetial deletion 15q11-13Prader-Willi

Angelman

Maternal

Paternal

Chromosome 15

Deletion

Characteristicposture

Inverted V-shaped upper lip small hands feet and obesity

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Consanguinity

bull Increases the chance that a mating couple

will both carry the same disease gene

bull Seen more frequently in pedigrees involving

rare recessive diseases than in those

involving common recessive diseases

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth

Phenocopy

bull Phenocopies ndash environmentally produced

phenotypes that mimic mutations

bull Environmental factors can influence genetic

expression after birth

Poor nutrition can effect brain growth body

development and height

Childhood hormonal deficits can lead to

abnormal skeletal growth