faculty of biochemistry and molecular medicine: molecular ... · • delayed development, ... •x...

1

Sanna Karppinen

13.11.2017

Inheritance patterns II 2

Mitochondrial (lectured elsewhere)

Multifactorial inheritance 2

Untypical ways of inheritance 6

Glossary of terms 15

Faculty of Biochemistry and Molecular Medicine:Molecular, cell biological and genetic aspects of diseases

2

Despite accidents and typical infections heritable elements

are involved in all diseases

• Congenital malformations, common adulthood diseases

• The amount of genetic and environmental factors varies

• Appear in families or in certain population, but inheritance doesn’t

follow any pattern

• polygenic vs. multifactorial?

GENETIC FACTORS

ENVIRONMENT

100%

4. Inheritance patterns II: Multifactorial inheritance

Monogenic vs Multifactorial

In multifactorial diseases

• inheritance pattern is not

so clear, because many

genes and environmental

factors affect the

manifestation

• Pathogenic mechanisms

are complicated

• Etiologic heterogenity:

Same or similar

phenotype may originate

from different factors

4. Inheritance patterns II: Multifactorial inheritance 3

Multifactorial diseases

Disease phenotype

Effect of many genes

“Environmental factors”

Activity

Stress Smoking

other

Gene +

Gene +

Gene -Gene +Gene+

Gene -

S. Solovieva

4. Inheritance patterns II: Multifactorial inheritance 4

Example of epistasisCoat color is controlled by two genes:

• E gene: pigment or no pigment work first

• B gene: the amount of pigment effect depends on E gene

4. Inheritance patterns II: Multifactorial inheritance

These two genes are epistatic,

which means that the expression

of one of the genes is dependent

upon the expression of the other.

5

https://online.science.psu.edu/sites/default/files/biol011/Fig-6-16-Epistasis_0.jpg

6

1. DNA repeat expansions and human diseases (will be

lectured as own topic later)

• anticipation = the symptoms of the genetic disorder appear

younger and severity of symptoms increases in each

generation

2. Genomic imprinting

• Expression of a gene is regulated by a parent-of-origin-

specific manner (linked to sex of parent)

• The activity of a gene in a genepair depends on whether

the gene locates in maternal or paternal chromosome

• Methylation of other allele during female/male meiosis:

methylated gene is inactivated• May results in disease, if the only active allele is inactivated or

deleted

• Many are tissue specific

• About 100 genes known, as large groups in genome (e.g.

genes encoding RNA modifying proteins, proteins regulating

tissue growth and brain functions)

CH3

♀ ♂

4. Inheritance patterns II: Untypical ways of inheritance

http://www.geneimprint.com

7

Prader-Willi (PWS) ja Angelman (AS)

syndromes

• frequencies 1:10 000 – 30 000

• Congenital multi-anomaly syndromes

• Genes of the syndromes locate in the same

chromosomal region 15q11-12, 6 imprinted

genes

• Paternal deletion in region 15q11-12 causes

Prader-Willi syndome and maternal deletion

Angelman’s syndrome

• In PWS patients, deletion in paternal

chromosome, mother´s chr inactivated (four

paternally expressed genes)

• In AS patients, deletion in maternal

chromosome, father´s chr inactivated (two

maternally expressed genes)

CH3

♀ ♂

PWS

AS

CH3

♀ ♂

Genomic imprinting


Prader-Willi syndrome (PWS): • PWS gene normally paternally active, maternal inactive• Deletion in paternal allele or both alleles are inherited from mother

(UPD) disease• mild to moderate intellectual impairment and learning disabilities,

obesity, hypogenitals

Angelman syndrome (AS):

• Normally maternal gene active, paternal inactive

• Deletion in maternal allele, or both alleles are inherited from father

(UPD) disease

• delayed development, intellectual disability, severe speech

impairment, and problems with movement and balance

ATP10A

+


Genomic imprinting: Prader-Willi (PWS) ja Angelman (AS) syndromes

8

X-chromosomal inactivation = Lyonization• About two weeks of age in every cell of a

female embryo, one of the two X chrs are inactivated

• Guarantees equal gene dosages both in males and females

• X chr is silenced by packaging it into a transcriptionally inactive structure called heterochromatin

• irreversible → cell herited, similar in every daughter cell (Reversed during oogenesis)

• Females are mosaics: in some cells genes from paternal X-chromosome are expressed and in other cells those from maternal X chr

• If one X-chr contains mutation, part of the cells still have normal allele and gene function

• Not all X-chromosomal genes are inactivated homologs in Y chr

• X-chromosomal inherited diseases: due to abnormal inactivation, a woman carrying X chr recessive trait may manifest the disease (if one X is mutated and the one with normal allele is inactivated in most of the cells)

4. Inheritance patterns II: Untypical ways of inheritance 9

10

Other mechanisms of untypical inheritance:

Prion diseases (will be lectured as own topic later)

Gonadal/germ line mosaikism

• Parent may have mutation in gonads as a mosaic, so that among

the normal germ line cells there is a cell line with altered genome

Uniparental disomy (UPD)

• Person has two copies of a chromosome from one parent and no

copy from the other parent

• Arises from a meiotic chromosome segration defect

(nondisjunction I/II)

• May cause a disease in the case of imprinted genes


Uniparental disomy (UPD)

• Trisomy rescue (loss of onehomologue) can lead to UPD

• UPD can arise also in fertilization, if one gamete is disomic and other nullisomicfor same chromosome

• Child can be homozygous for recessive trait, eventhoughonly one parent has the genedefect being healthy carrier

Cystic fibrosis

4. Inheritance patterns II: Untypical ways of inheritance 11

12

What is the most probable pattern of inheritance in the following pedigrees? Explain why.

Exercise 5.

Questions

• How many genes human have?

• What is a gene?

• Which factors damage DNA?

• What kind of DNA damages there are?

• How different mutations in a gene may affect the gene

product?

• How does dominant/recessive allele affect disease

phenotype?

• X chromosomal inheritance?

• Genomic imprinting, how does it affect disease phenotype?

• What means lyonisation?

• What means uniparental disomy and how it arises?

13

Glossary of terms

• gene locus

• allele

• genotype

• phenotype

• homozygous (AA, aa, +/+, -/-)

• heterozygous (Aa, +/-)

• dominant

• recessive

• autosomal

Gene locus

2 alleles

14

http://www.google.fi/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCPT2mrOk4MgCFUfXLAodxtwBPA&url=http://www.bbc.co.uk/schools/gcsebitesize/science/edexcel_pre_2011/genes/genesrev1.shtml&psig=AFQjCNGieaWnk7S48z6nQslvt4epulE6rQ&ust=1445953800902169

• penetrance

• polymorphism

• X-chromosomal

• carrier

• pedigree

• mitochondrial inheritance

• monogenic

• polygenic (multifactorial inheritance)

• epistasis

Glossary of terms

15

Chromosomal mutations and disorders

Sanna Karppinen

13.11.2017

16

Faculty of Biochemistry and Molecular Medicine:

Molecular, cell biological and genetic aspects of diseases

5 ECTs

17

Chromosomal mutations and disorders 17

Chromosome/genome number changes 20

Errors in the division of chromosomes 24

Autosomal chromosomes 24

Sex chromosomes 34

Structural abnormalities of chromosomes 38

Questions 50

Content of the lecture:

Aims for this part:

• learn the most common chromosomal disorders related

to number changes of autosomes and sex

chromosomes

• get familiar with the different kind of chromosomal

mutations and learn how they arise

18

Chromosomal abnormalities:

• microscopically detectabele change in karyotype

Chromosomal diseases:

• Chromosomal abnormalities lead to excess or loss

of genetic material causing harm for the function orhealthiness of tissue, organ or individual

• Congenital abnormalities, but usually not inheritable

• Develope during fertilisation or before it

• Esiintyvyys riippuu tarkasteluajankohdasta:

• 50% of abortions during first trimester show

chromosomal anomaly

• 0.6% of the live-born have

chromosomal anomaly

• Numerical abnormalities

• Structural abnormalities

4. Chromosomal diseases

• 0.2 % of newborns have a

chromosomal anomaly with

symptoms

• 0.2% symptoms during

childhood or teenage

• 0.2% symptomless changes

19

Aneuploidy= abnormal number

of chromosomes

– extra or missing

chromosome(s)

numerical abnormality

Diploid (2N)

Nullisomic (2N-2)

Monosomic(2N-1)

Double monosomic (2N-1-1)

Trisomic (2N+1)

Tetrasomic (2N+2)

Normal set of metaphase chromosomes

Aneuploidy

4. Chromosomal diseases: number changes

Variations in number of complete chromosome sets

20

Diplod (2N)

Normal chromosomes

Monoploid - only one set of chromosomes (haploid)

Polyploid - tree or more sets of chromosomes

Triploid (3N))

Tetraploid (4N)

Monoploid (N)


21

Somatic cell: diploid 2N

Gamete: haploid 1N

Some somatic cells are polyploidic:

• megakaryocytes (16-128n)

• Polyploidy seems to increase thedevelopment of platelets

• hepatocytes (4n-8n)

• Reason is not understood:

prabably for protection of geneticmaterial or gene expression

• Muita kudoksia:

• cardiomyocytes (4n)

• big trofoblasts (8n-64n)

• Purkinjen cells (4n)

• Retinal ganglion cells (4n)

• muscle cells may contain even

hundreds of diploid nuclei in one cell

Cancer cells contain clonal

chromosomal abnormalities


http://www.google.fi/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiYn6-WxJPXAhVLIlAKHR8TCuYQjRwIBw&url=http://slideplayer.fi/slide/5180498/&psig=AOvVaw2ubV0gzVFQuLwfqtOxdVn4&ust=1509287468237581

22

Genome number changes are harmful for embryo development

• Triploidy (3n = 69) may occur, if diploid premature egg cell is fertilised,

or haploid egg is fertilised by two sperm cells at the same time

• Molar pregnancy (non-viable fertilized egg implants in the uterus and

will fail to come to term) may occur from a tsygote having two paternal

and no maternal genome

• Ovarial teratoma: tumor having a diploid egg, which starts to divide

parthenogenetically

• Chimera: fusion of two fertilised tsygotes

• While in monotsygote twins the tsygote divides to form twoembryos developing in uterus separately


23

Autosomes

• Single number differences in

chromosomes (aneuploidy) are the

most common reasons for both

miscarriages and for chromosomal

disorders

• Defect in meiosis (nondisjunction)

leads to gamete having one

chromosome too much or missing one

chromosome

if this cell participates in

fertilisation, the result is trisomy

(2n=47) tai monosomy (2n=45) for

the corresponding chromosome

• If the defect occurs later → transmitted

to progeny → mosaicism

• Female meiosis is long prone to

chromosomal abnormalities

• Trisomies for chromosomes 13, 18 and

21 are found in live-born babies (and

rare mosaics of trisomies for

chromosomes 8 and 9)

Meiosis I

Meiosis II

Meiosis I

Meiosis II

TRISOMY MONOSOMY

fertilisation

4. Chromosomal diseases: errors in the division of chromosomes

• Defect in I meiotic division:

• Chromosome pair in same pool

diploid ja nullisome gametes

• Errors at meiosis I are the most

common cytologic explanation for

trisomies.

• Most trisomies show a maternal

age effect, and the advanced

maternal age correlates positively

with errors at meiosis I

• 90% chr. 13 ja 21 trisomies:

maternal, generally defects in

meiosis I

trisomic monosomic

gamete


First meiotic division

Defect in II meiotic

division :

• One extra chromosome or

one chromosome loss

• Errors at meiosis II are less

common among

aneuploidies.

• 90% chr.18 trisomies

maternal 2/3 defects in

meiosis II

trisomicmonosomic

gamete

normal

Second meiotic division


26

Trisomy 21, Down syndrome

• incidence 1:600

• often defect in the I division of meiosis, in 80% cases maternal

• The age of mother correlates with the risk of trisomy-21

• about 5 % of the Down patients have trisomy mosaicism,

translocation or other structural defect in the chr 21

• Mosaics have milder symptoms


Exercise 6.

Why mother´s age is associated with higher risk of for a

baby to have chromosome anomalies than with father´s

age?



• Critical genes for the syndrome locate in region

21q22

• 21q22.1-q22.3: 289 genes

• DSCR1 (Down Syndrome Critical Region gene1):

causes intellectual disability and heart defects

• Overexpressed in brains of Down fetuses

• DSCR4: affects development of morphologic

features, hypotonia and intellectual disability

• Expressed mainly in placenta

• Severity of symptoms vary, life time about 40

years (~ 50%)

• Intellectual disability, fastened aging

• Infections, heart problems (not all), dysfunction

of intestinal tract

• Females are fertile, men not

http://www.answers.com/topic/down-syndrome


http://en.wikipedia.org/wiki/File:Down_syndrome_lg.jpg

Function of DSCR1

Nature 441, 582-583(1 June 2006)Normal Down syndrome

DSCR1 and also DYRK1A

29

Protein affects the transcription of genes by inhibiting thecalsineurin dependent signaling pathway and thuspossibly disturbs the development of central nervoussystem



Trisomy 13, Patau syndrome

• 1/10 000 – 20 000

• In 75% of cases extra chr. 13

• translocation 20%, some inherited

• mosaic 5%, incomplete extra chromosome

• Lethal or severe developmental defect• Microcephaly

• Cleft lip and palate

• failure of the forebrain to divide properly

• Severe heart defect

• Abdominal, genital and kidney defects

• Survival about 1-2 months


Trisomy 18 / Edwards syndrome

• More common that trisomy 13, 1: 5000

• ~ 95 % clear trisomies and 5 % mosaic cases

• Partial trisomy 18 due to translocation (~2%)

• Smallest extra region of chr.18 that causes the

syndrome is q21-22

• Brain anomalies , Microcephaly

severe developmental disbility

• Heart defects (~90%)

• clenched hands

• “rocker bottom feet”

• lifetime1-2 months, death latest at 1year of age


Sex chromosomes

• Single number changes or structural abnormalities of sex chromosomes

are less harmful than those in the other chromosomes

• Mostly do not harm embryo development but appear later in the life

• Y chromosome contains low number of genes

• Inactivation of X chromosome

• Sex chromosomes, X and Y, determine the genetic characteristics of sex-linked traits

• SRY-part (pter-q11.2) of Y contains genes that direct the development of

the masculine features without femine phenotype

→ mild developmetal disoders, even harmless, symptoms during

childhood or at teenage

• X and Y share sequence homology segments, pseudoautosomalregions (PAR1, 2, 3)

• inherited in the same manner as autosomes

• in males, pairing and recombination are restricted to the PARs• Deletion of PAR1 is associated with total male sterility

• Reduced recombination in PAR1 can lead to aneuploid sperm, which can cause X-

chromosome monosomy (Turner syndrome) or XXY (Kleinfelter syndrome) in the

offspring

recombination is necessary in males

32

European Journal of Human

Genetics (2008) 16, 771–779

SRY


Sex chromosome

abnormalities

In men:

• 47,XXY (Klinefelter

syndrome)

• 47, XYY

• 46,XY/45,X-mosaicism

In women:

• 45,X-monosomy

(Turner´s syndrome)

• 47,XXX

• 48,XXXX and 49,XXXXX

• 46,XY-naiset

45, X Turner´s syndrome

• 45, X, mosaicism• mosaicism allow the survival in utero: placental rescue cell line

46, XX

• loss of genes in PAR1 affect development of placenta lethality

• Incidence 1: 2500 newborn girls, more common in miscarriages (8.6% vs 0.04%)

• Poorly developed, fibrotic gonads lack of germ cells and ovarian follicles no oocytes

• Activity of two active X chrs are needed to maintain the germ cells and later ovaries

• No estrogen synthesis lack of female features• No puberty without hormone therapy (estrogen and progesterone)

• Somatic abnormalities due to abnormal dosage of PAR genes• Short stature (<150 cm) SHOX important for bone

development and growth

• Lymphedema of the hands and feet

• Heart defect


47, XXY Klinefelter syndrome

• Most common sex chromosome alteration in males

• 47, XXY 1: 500-1000 newborn males

• 48, XXXY, or 49, XXXXY: variant formsmore severe signs and

symptoms

• Extra copies of X chromosome are inactivated

• Extra copies of genes on the X chr. interfere with male sexual

development often prevent testes to function normally

reduce the levels of testosterone

• Affects male physical and cognitive development

• Infertile, small testes

• Slightly feminized physique (breast development, wide hip)

• Poor muscle tone

• Tall stature

• Some have learning and psychological problems

• Testosterone treatment to improve musculine phenotype,

concentration and strenght

• Not inherited


https://www.google.fi/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiqvdqf2NnPAhWOOSwKHeiDDucQjRwIBw&url=https%3A%2F%2Fwww.emaze.com%2F%40ALFTFTRO%2FKlinefelter-Syndrome&psig=AFQjCNFWtABcSklCf40RHBNRjjsTjdhW-w&ust=1476513407397806

47, XYY

• 1:1000 newborn males

• Affected usually very tall

• severe acne during adolescence

• Fertility and sexual development

are normal normal physical

appearance

• May include learning disabilities

and behavioral problems such

as impulsivity

• Not inherited


36

• DNA damage is common phenomenon in

living cells

• damage occuring during DNA

replication or recombination event may

remain unrepaired or is repaired

incorrectly

• Types of structural abnormalities :

• Balanced: translocations, inversions

• Unbalanced: deletions, duplications,

insertions (occur in all chromosomes)

• Can be inherited, 60-70 %

• unbalanced gametes in meiosis →

disease to progeny

• Geno- and phenotype depends on

how the genetic material of the

parents is divided in meiosis

• Of the clinically relevant cases 1/3

are new alterations, 2/3 inherited

4. Chromosomal diseases: Structural abnormalities of chromosomes

Structural abnormalities of chromosomes

37

Translocationshttps://www.youtube.com/watch?v=MLDCJ2gUC84

• Translocations involve the breakage

and rejoining of two or several

chromosomes

• In balanced translocation there is an

equal exchange of chromosomal

material

Reciprocal translocation: the

location of a gene changes, but the

amount of genetic material is

unaltered

• Doesn’t usually cause problems for a

carrier, but a progeny may be

affected


• Most often either normal or

translocation carrier

chromosomes are inherited• Other distributions lead to

non-balanced chromosomes

miscarriage

https://www.youtube.com/watch?v=MLDCJ2gUC84

38

Examples of translocations

• t(1;8)(q32;q22)

• In Finnish families, > in 10 generations

• Causes miscarriage in 30 % of the pregnancies of carriers

• No chromosomal diseases have been observed in the family

• t(4;11)(q21;p13)

• Normal , can cause problems for progeny

(mixed lineage leukemia)


Example: t(4;11)(q21;p13): meiosis

• Translocation chromosomes have aligned withhomologous chromosome segments in the division planeand a tetravalent is formed.

• What kind of segregation possibilities there are in the I division?

Normal situation

39

Jukka Moilanen (http://www.oppiportti.fi/op/ltg01005/do)


Example: t(4;11)(q21;p13): meiosis

• (A) alternate type balanced chromosomes in gametes

• produces normal gametes, or gametes with the parental balanced translocation. The baby will have a normal phenotype .

• (B, C) adjacent types Association of normal chromosome with rearranged

• gives rise to "duplication-deficiency": an excess of some bits and a lack of other bits → changes in the amount of genes

40

Aalternate type

Badjacent 1 type (frequent)

Cadjacent 2 type, (rare):

normal T carrier Extra 411 deficiency

Extra 114 deficiency




Robertsonian centric translocation

• Specific type of translocation: fusion of 2 acrocentric chromosomes (chr 13, 14, 15, 21, 22) • Long arms fuse very close to the centromeres rearranged

chromosome includes the long arms (translocation chromosome containing the short arms is lost)

• no phenotypic effect, acarrier has 45 chromosomes but gene dosage does not change

• Frequency 1:1000

• t(13;14)(p10;q10)• carriers 1:1500

• Predisposes to trisomy 13 ja miscarriage, mild infertility

• t(14q;21q), most frequent• In carrier pregnancies 20% risk for extra

copy of chr. 21 (Down syndrome)


lost

42

Chr 14 Chr 21

Normal

chromosomes

Balanced

14/21 carrier

14/21 21 14

21 14

Normal

21

14 deficiency

Lethal

14

21 deficiency

Lethal

14/21 14

Extra 14

Lethal

Possible

gametes

Results in…

14/21

Carrier

14/21 21

Extra 21

Down


• Carrier of the translocation is

phenotypically normal, but has deficiency

in fertility

• Carrier may produce six different types of

gametes

• 1/6 of the gametes have normal

chromosomes, 1/6 has translocation chr

and four are aneuploids

Meiosis in the carrier of Robertsonian transloction t(14;21)

I division I division I division

43

43

Chromosomal abnormalities

have a role in cancer cell

development

t(9;22), Philadelphia

chromosome

• Many known pathological

translocations are balanced

resiprocal translocations

• Philadelphia chromosome: resiprocal

translocation between chr 9 ja 22

t[9,22][q34;q11]

BCR-ABL fusion gene (breakpoint

cluster region Abelson leukemia

viral proto-onkogene)

uncontrollable division of cells,

leukemia

• found only in cancer cells


44

Translocation Associated diseasesFused genes/proteins

First Second

t(8;14)(q24;q32) Burkitt's lymphoma

c-myc on chromosome 8,

gives the fusion protein

lymphocyte-proliferative ability

IGH (immunoglobulin heavy locus) on

chromosome 14,

induces massive transcription of fusion protein

t(11;14)(q13;q32) Mantle cell lymphoma

cyclin D1 on chromosome 11,

gives fusion protein cell-

proliferative ability

IGH (immunoglobulin heavy locus) on

chromosome 14,

induces massive transcription of fusion protein

t(14;18)(q32;q21)Follicular lymphoma (~90% of

cases)

IGH (immunoglobulin heavy

locus) on chromosome 14,

induces massive transcription of

fusion protein

Bcl-2 on chromosome 18,

gives fusion protein anti-apoptotic abilities

t(10;(various))(q11;(various)) Papillary thyroid cancer RET proto-oncogene on

chromosome 10

PTC (Papillary Thyroid Cancer) - Placeholder for

any of several other genes/proteins

t(2;3)(q13;p25) Follicular thyroid cancerPAX8 - paired box gene 8 on

chromosome 2

PPARγ1 (peroxisome proliferator-activated

receptor γ 1) on chromosome 3

t(8;21)(q22;q22)Acute myeloblastic leukemia

with maturationETO on chromosome 8

AML1 on chromosome 21

found in ~7% of new cases of AML, carries a

favorable prognosis and predicts good response

to cytosine arabinoside therapy

t(9;22)(q34;q11) Philadelphia

chromosome

Chronic myelogenous leukemia

(CML), acute lymphoblastic

leukemia (ALL)

Abl1 gene on chromosome 9[15] BCR ("breakpoint cluster region" on

chromosome 22

t(15;17)(q22;q21) Acute promyelocytic leukemia PML protein on chromosome 15

RAR-α on chromosome 17

persistent laboratory detection of the PML-

RARA transcript is strong predictor of relapse

t(12;15)(p13;q25)

Acute myeloid leukemia,

congenital fibrosarcoma,

secretory breast carcinoma,

mammary analogue secretory

carcinoma of salivary glands

TEL on chromosome 12 TrkC receptor on chromosome 15

t(9;12)(p24;p13) CML, ALL JAK on chromosome 9 TEL on chromosome 12

t(12;21)(p12;q22) ALL TEL on chromosome 12 AML1 on chromosome 21

t(11;18)(q21;q21) MALT lymphoma API-2 MLT

t(1;11)(q42.1;q14.3) Schizophrenia

t(2;5)(p23;q35) Anaplastic large cell lymphoma ALK NPM1

t(11;22)(q24;q11.2-12) Ewing's sarcoma FLI1 EWS

t(17;22)dermatofibrosarcoma

protuberansCollagen I on chromosome 17

Platelet derived growth factor B on chromosome

22


Translocations in cancer

https://en.wikipedia.org/wiki/Chromosomal_translocation#cite_note-pmid12755554-15

Unbalanced translocation

• Unequal exchange of chromosome material

extra or missing genes = deletions and duplications

• Extra gene material (>4%) or missing material(>2%): miscarriage

• Small alteration (microdeletion/ duplication): chromosome disease

• Usually sporadic, with mild phenotype, inheritablechanges

•Deletions of short arm of chr. 4 and 5: intellectualdisability

•Prader-Will: 15q11-13 paternal deletion

• intellectual disability, over-weight, special features

•Angelman syndrome: 15q11-13, maternal deletion

• severe intellectual disability, epilepsy, anxiety, specialfeatures


Inversions• If two breaks occur in one

chromosome

the region between the breaks

may rotate 180 degrees before

rejoining with the two end fragments

the overall amount of the genetic

material is not changed

• inv9(p11;q13), most common in

general population, 1 -3%,

• always inherited as an balanced

form

• no recombination

• clinically inrelevant

• Clinically relevant appear in the

cases of infertility or

phenotypically abnormal child


• Recombination doesn’t

happen in short inversion

• In long inversions,

inversion chromosome

aligns with homologous

chromosome

inversion loop

crossing-over

deletions or duplications


Inversions

Questions• What effects can extra chromosomal material have?

• What means Robertson´s translocation?

• How can be a Down syndrome inherited from a parent

to child?

• What happens in reciprocal translocation?

• What means unbalanced translocation?

• What is a Philadelphia chromosome?

48

faculty of biochemistry and molecular medicine: molecular ... · • delayed development, ... •x...

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