Genetics

Kenneth Lyons Jones

Department of Pediatrics

University of California, School of Medicine

La Jolla, CA

Purpose of a Diagnosis

• Prognosis – what does thiscondition mean to my child

• Recurrence risk – what are mychances of having another childwith a similar condition

XXY Syndrome

• Performance. I.Q from well below to well above average. Mean full-scale I.Q. between 85 and 90. Tendency toward behavior problems,especially immaturity, insecurity, shyness, poor judgment, andunrealistic boastful and assertive activity. The formation of peerrelationships is difficult. Problems with psychosocial adjustment areincreased, although significant psychiatric difficulties are not oftenencountered.

• Growth. Tendency from childhood toward long limbs, with low upperto lower segment ratio and relatively tall and slim stature.

• Hypogonadism with Hypogenitalism. Childhood: Relatively smallpenis and testes. Adolescence and adulthood: Testes remain small.With rare exception, testosterone production is inadequate. Infertilityis the rule. Virilization is partial and inadequate.

XYY Syndrome

• Growth. Acceleration in midchildhood.

• Performance. Dull mentality. Full-scale I.Q. is withinnormal limits although usually lower than siblings (range,80 to 140). Relative weakness, with poor fine motorcoordination and sometimes a fine intentional tremor.Speech delay common. Learning disabilities (50 percent).

• Dentition. Large teeth.

• Skin. Severe nodulocystic acne at adolescence.

Natural history

• Tall stature evident after 5 to 6 years of age.• Affected boys are usually not strong or well coordinated

and tend to have poor development of the pectoral andshoulder girdle musculature.

• Behavioral problems, especially distractability,hyperactivity, and temper tantrums are present inchildhood and early adolescence. Aggressive behavior isnot usually a problem and they learn to control anger asthey get older.

• Onset of puberty is approximately 6 months delayed.Heterosexual activity is normal. The majority of 47,XYYmales are fertile and have chromosomally normaloffspring.

Comment

• Although early reports suggested thatthere existed an overrepresentation of47XYY individuals among institutionalizedmale juvenile delinquents, prospectivelongitudinal studies of unselected 47XYYmales suggest that behavior disorders arenot a significant problem for theseindividuals in childhood and adolescence.

Etiology

• The diagnosis is confirmed bychromosomal analysis revealing a 47XYYkaryotype

Imprinting

A phenomenon whereby certaingenes are marked differentlyduring male vs female germcell formation so thatapparently identical genespossess dissimilar functiondepending on whether theypass from the mother or thefather

Imprinting (continued)

• Imprinting commonly serves to “turn off” agene or reduce its function

• It plays a role in a number of humansyndromes including:

Prader-Willi syndrome

Angelman syndrome

Beckwith syndrome

• There are estimated to be between 100 and200 imprinted genes in the mammaliangenome

Imprinting (continued)

• Imprinting was first identified in the mouse• Nuclear material removed from egg• Two maternal copies of the genome were inserted in the

egg of one mouse• Two paternal copies of the genome were inserted in the

egg of a second mouse• The offspring of the two mice were very different

Mouse with two maternal copies – relatively normal size embryowith small

placentaMouse with two paternal copies – severely under-grown embryo with

relativelynormal size placenta

Conclusion: The paternal genotype is responsible for theplacenta

The maternal genotype is responsiblefor the embryo

PPMM

Large PlacentaUnder-grown Embryo

Small PlacentaNormal size Embryo

Uniparental Disomy

A situation in which both copiesof a given gene or chromosome comefrom the same parent. It isvirtually always the result of theloss of one chromosome from atrisomic conceptus (rescue).

maternal disomy

maternalchromosomes

paternalchromosome

normal normal

paternal disomy

maternalchromosome

paternalchromosomes

normal normal

Prader-Willi Syndrome

• Growth. Normal birth length with deceleration in the first 2-months of life andcontinued fall-off in adolescence.

• Obesity. Onset from 6 months to 6 years.• Craniofacial. Almond-shaped upslanting palpebral fissures, Narrow bifrontal

diameter. Strabismus.• Hair, Eye, and Skin. Blond/light brown hair, blue eyes, fair sun-sensitive skin.

Picks excessively at sores.• Performance. MR mild (63), moderate (31%), and severe (6%). Three quarters of

affected individuals receive special education and function at a six-grade level orbelow in reading and third-grade or below in math. Food-related behavior problemsincluding excessive appetite, absent sense of satiation, obsession with eating.Hypotonia, severe in early infancy.

• Hands and Feet. Small.• Genitalia. Small penis and cryptorchidism.

• Other. Temperature instability. High pain threshold. Skill with jigsaw puzzles.

Etiology of Prader Willisyndrome

• Maternal PWS allele at 15q11-13 isnormally imprinted or turned off.

• The following mechanisms result inPWS

1) paternal deletion of 15q. Thematernal

allele remains but it isimprinted

2) maternal UPD (two maternalcopies and

no paternal copies of 15q)3) mutation in the imprinting

center or atranslocation involving

Molecular Evaluation

• Methylation analysis detects all three defects

• If methylation pattern abnormal, FISH used todocument a deletion, and microsatellite probesused to confirm maternal disomy

• Abnormal methylation analysis and normal FISHand UPD studies indicate an imprinting defect

• Recurrance risk negligible except in rare case ofchromosomal translocation or in case ofimprinting center mutation

Comment

• Compared to children with del 15q, those withUPD15 are less likely to be:

-hypopigmented

-have the typical facial features

-show skin picking

-skill with jigsaw puzzles

-high pain threshold

HOWEVER, they are more likely to havepsychotic illness

Angelman Syndrome

• Performance. Severe mental retardation with marked delay in attainmentof motor milestones (100 per cent). Paroxysms of inappropriate laughter.Absent speech or less than six words (100 per cent).

• Craniofacial. Microbrachycephaly. Blond hair (65 per cent). Decreasedpigmentation of the choroid and iris, the latter resulting in pale blue eyes(88 per cent). Maxillary hypoplasia, deep-set eyes, a large mouth withtongue protrusion and widely spaced teeth. Prognathia.

• Neurologic. Ataxia and jerky arm movements resembling a puppet gait(100 per cent). Characteristic position of arms which are upheld withflexion at wrists and elbows. Seizures beginning between 18 and 24 months(86 per cent). Characteristic EEG abnormalities (92 per cent).

Etiology of Angelmansyndrome

• Paternal allele at AS critical region isnormally imprinted or turned off

• The following mechanisms result in AS1) maternal deletion of 15q11-13.

Paternalallele remains but is imprinted

2) Paternal unipaternal disomy ofchromosome 15

3) imprinting center mutation

Comment

-Patients with chromosome 15 deletions aremore severely affected with a higher incidenceof seizures, microcephaly, andhypopigmentation.

-A response to the standard physician issuetuning fork held close to their ear, including awide smile, laughter, and a tendency to leantoward the vibrating tuning fork, has beendocumented and can be used as an adjunct testfor this disorder in children as young as 12months of age.

Recurrence Risk

• Except for the following situations, allcases are sporadic:

1) a chromosomal rearrangement or

unbalanced translocation in which the

same rearrangement occurs in the

mother

2) an inherited imprinting center

mutation

Beckwith Syndrome

• Performance. Unknown incidence of mild to moderate mental retardation;may be normal.

• Growth. Macrosomia with large muscle mass and thick subcutaneoustissue.

• Craniofacial. Macroglossia. Prominent eyes with relative infraorbitalhypoplasia. Capillary nevus flammeus, central forehead and eyelids.Unusual linear fissures in lobule of external ear. Indentations on posteriorrim of helix.

• Hyperplasia and Dysplasia. Large kidneys with renal medullarydysplasia. Pancreatic hyperplasia, including excess of islets. Fetaladrenocortical cytomegaly—a consistent feature. Interstitial cellhyperplasia, gonads.

• Other. Neonatal polycythemia. Hypoglycemia in early infancy (about onethird to one half of cases). Omphalocele or other umbilical anomaly.

Etiology

- Although usually sporadic, autosomaldominant inheritance occurs in about 10%to 15% of cases.

- BWS is caused by perturbations of thenormal dosage balance of a number ofgenes clustered at 11p15, a highlyimprinted region in the genome.

- Genes at 11p15 are organized in twoseparately controlled imprinted domains.

Domain 1

Domain 1 contains paternally expressed insulin-like growth

factor 2 (IGF2), as well as a number of genes and

transcripts that control expression of IGF2.

Mechanisms that increase expression of paternally

expressed IGF2 all lead to BWS:

-maternally derived translocations and inversions of

chromosome 11p15

-Duplications of the paternal chromosome 11p15,

-Paternal uniparental disomy (20% of cases of BWS)

-Imprinting anomalies that increase expression of

IGF2,

Domain 2

• Domain 2 contains several imprintedgenes including:

CDKNIC – 10% of sporadic cases and40% of dominant cases are due to amutation of this gene

LIT1 – A paternally expressed transcriptthat regulates the expression of othergenes in Domain 2. (Loss of imprint ofLIT1accounts for 40% to 50% of BWS)

Williams Syndrome

:

• Growth. Mild prenatal growth deficiency. Postnatal growthrate about 75 per cent of normal

• Performance. Average I.Q.- 56, (range 41 to 80). friendlyloquacious personality; anxious; hoarse voice; hypersensitivityto sound; Level of general language ability is much greaterthan general cognitive ability.

• Facies. Periorbital fullness of subcutaneous tissues. Blue eyes,stellate iris pattern. Anteverted nares, long philtrum, prominentlips with open mouth.

• Cardiovascular. Supravalvular aortic stenosis, Renal arterystenosis with hypertension, hypoplasia of the aorta, and otherarterial anomalies.

• Dentition. Partial anodontia, microdontia,.

Behavioral Problems

• In early infancy, these children tend to befretful, have feeding problems, vomitfrequently, are constipated, and are oftencolicky.

• During childhood they tend to be outgoingand loquacious, easily approachstrangers, and have a strong interest inothers.

.

Morbidity and Mortality

• Progressive medical problems are the rule in adults.These include hypertension; progressive joint limitations;recurrent urinary tract infections; and gastrointestinalproblems including obesity, chronic constipation,diverticulosis and cholelithiasis, and hypercalcemia. Thevast majority live with their parents, in group homes, or insupervised apartments.

• Sudden death has been documented in a number ofchildren. Some deaths were associated with theadministration of anesthesia. Health supervisionguidelines have been established for children withWilliams syndrome by the Committee on Genetics of theAmericam Academy of Pediatrics

Etiology

• Although most individuals with this disorder representsporadic cases within otherwise normal families, parent-to-child transmission has been documented.

• Both inherited and sporadic cases of Williams syndromeare caused by a deletion at 7q11.23, a region whichincludes approximately 17 genes.

• Hemizygosity for the elastin gene is responsible forsupravalvular aortic stenosis as well as other vascularstenosis, and LIM-kinase 1 hemizygosity is a contributingfactor to impaired visuospatial construction cognition inthis disorder. Many of the other features must be theresult of hemizygosity for other genes in the deletedregion. (A contiguous gene syndrome)

Tuberous Sclerosis

• Brain and Eyes. Glioma-angioma lesions in cortex and whitematter, seizures (93 per cent), mental deficiency (62 per cent).Behavioral problems and autism.. Hamartomas of retina oroptic nerve (53%); in half of these, the hamartomas arebilateral.

• Skin:Fibro-angiomatous lesions(83%) varying in color fromflesh to pink to yellow to brown, develop in the nasolabialfold, cheeks, and elsewhere. White macules classified intothree types: “Thumb-print” macules, “lance-ovate” macules(one end rounded, the other with a sharp tip) or ash leafmacule, and the confetti macules (tiny 1-to 3-mm macules).Café au lait spots.

• Renal. Angiomyolipomata in 45 to 81%, usually multiple andbenign.

• Dentition. Pit-shaped enamel defects, most evident by closeinspection of labial premolar surfaces.

Morbidity and Mortality

• An unknown percentage of patients dieprior to 20 years of age as theconsequence of status epilepticus, generaldebility, pneumonia, or tumor.

• There is wide variability in expression ofthe disease.

Etiology

• Autosomal dominant. About two-thirds of casesrepresent fresh mutations.

• Mutations in TSC1, located at 9q34 and ofTSC2 located at 16p13, encoding proteinsreferred to as hamartin and tuberin respectively,are responsible.

• Although the pathways in which these two genesparticipate have not been elucidated, they mostlikely represent tumor suppressor genes.

inheritedmutation

loss and reduplication

deletion

mutation in normal allele

somatic recombination

secondhit

Mechanisms for Tumorigenesis with

Tumor Suppressor Genes

Evaluation of 1st Degree Relatives

• Affected individuals usually show somemanifestations of the disorder by adulthood.

• A search for depigmented spots and/or hairs,enamel defects, and subungual hamartomas, aswell as MRI for periventricular lesions and renalultrasound for angiomyolipomas should beconsidered in first degree relatives of affectedindividuals prior to genetic counseling.

Neurofibromatosis, Type 1

• Skin. 6 or more café-au-lait spots over 5 mm in greatest diameterprior to puberty

• Tumors. Neurofibromas (a heterogeneous benign neural sheathtumor) occurring as discrete, dermal masses, focal cutaneous orsubcutaneous growths,

• Central Nervous System. Tumors, including optic pathway gliomas(1.5 to 7.5%) with median age of development 4.9 years) and otherastrocytomas, neurilemmomas, meningiomas, and neurofibromas.Mental deficiency in 2 to 5 per cent, with learning disability,hyperactivity, and/or speech problems in 50 per cent.

• Other. Lisch nodules or pigmented iris hamartomata (70% by 10years). Macrocephaly of postnatal onset. Mean IQ of 88..

• Skeletal. Scoliosis.

Natural History

• The majority of affected individuals have abenign course

• Diagnosis can almost always be made by 6years.

• Neurofibromas rarely develop in children lessthan 6 years of age, but are present in 48% of10 year olds and 84% of 20 year olds. Theymay increase in size and number at puberty,during pregnancy, and between 50 and 70 yearsof age.

Etiology

- Autosomal dominant with high penetrance butwide variability in expression.

- The neurofibromatosis type 1 (NF1) gene islocated at chromosome 17q11.2.

- About 50 per cent of patients have a fresh genemutation.

- The NF1 gene encodes a protein designatedneurofibromin, which may function as a tumorsuppressor.

Allelic Expansion

Describes the phenomenonin which the number ofcopies of a tandemlyrepeated sequence of DNA(usually 3-bp units)increases in numberduring cell division.Increase in the number ofrepeated sequences oftencreates instability and

Fragile X Syndrome

• Performance: IQ: males-30 to 55 sometimes mildlyretarded to borderline normal. Hand flapping or biting(60%) and poor eye contact (90%). ADHD. Autism(60%). IQ in Females-<70 in 30 to 50% with fullmutation.

• Craniofacial:Macrocephaly in early childhood.Prognathism usually not noted into after puberty. Largeears. Pale blue irides.

• Other: Macro-orchidism which becomes obvious afterpuberty

Etiology of Fragile Xsyndrome

• Expansion of trinucleotide repeat(CGG) in the promoter region of theFMR1 gene at Xq27.3

• Normal individuals have 6 to 54repeats

• Male and female premutation carriershave 54 to 200 repeats

• Affected individuals have >200repeats

• Expansion of premutations to fullmutations occurs only in femalemeiotic transmission

Trinucleotide Expansion Disorder with largeexpansion outside the coding region

Myotonic

dystrophy

CTG 5 to 37 100 to

>100

either,

congenital

maternal

3’ un-

translated

region

Friedreich

ataxia

GAA 7 to 22 200 to

>900

autosomal

recessive

intron

Fragile X

sydrome

CGG 6 to 52 200 to

>2000

maternal 5’ un-

translated

region

FRAXE GCC 6 to 35 200 or

more

usually

maternal

Trinucleotide Expansion Diseases with CAGexpansion in coding portion of the gene

Huntington

disease

CAG 6 to 34 36 to

>100

usually

paternal

exon

Spinal and bulbar

muscular atrophy

CAG 11 to 34 40 to 62 ususally

paternal

exon

SCA type 1 CAG 6 to 39 41 to 81 usually

paternal

exon

SCA type 2 CAG 15 to29 35 to 59 exon

SCA type 3

Machado-Joseph

CAG 13 to 36 68 to 79 usually

paternal

exon

SCA type 6 CAG 4 to 16 21 to 27 exon

Haw River

syndrome

CAG 7 to 25 49 to 88 usually

paternal

exon

CytoplasmicInheritance

- Describes the property ofgene transmission through thetransfer of cytoplasmicrather than nuclear material.Mitochondria and chloroplastscontain DNA that iscytoplasmically inherited.

- In that the egg but notthe sperm contains cytoplasm,transmission occurs onlythrough females

Mitochondrial Inheritance

Signs and Symptoms

Brain: developmental delay; dementia; seizures; neuro-psychiatric disturbances; atypical CP; migraines; strokes

Nervous system: weakness (often intermittent);neuropathic pain; absent reflexes; dysautonomia; GIproblems (GE reflux; diarrhea; irritable; constipation;pseudo-obstruction); fainting; absent or excessivesweating resulting in problems in temperature regulation

Muscles: hypotonia; cramping; muscle pain

Kidneys: renal tubular acidosis or wasting leading to lossof protein, magnesium, phosphorous, calcium, and otherelectrolytes

Signs and Symptoms(continued)

• Heart: cardiac conduction defects; cardiomyopathy

• Liver: hypoglcemia, liver failure

• Eyes: visual loss and blindness

• Ears: hearing loss and deafness

• Endocrine: diabetes; exocrine pancreatic;hypoparathyroidism

• Other: failure to thrive; short stature; respiratorydifficulties; vomiting

Types

• Mitochondrial myopathies

• Diabetes mellitis and deafness

• Leber hereditary optic neuropathy

• Leigh syndrome

• Neuropathy, ataxia, retinitis pigmentosa,and ptosis

• Myoneurogenic gastrointestinalencephalopathy

Fetal Alcohol Syndrome

• Growth

– Prenatal Growth Deficiency

– Postnatal Growth Deficiency

– Microcephaly

• Performance

– Developmental Delay

– Fine Motor Dysfunction

• Face

– Short Palpebral Fissures

– Long, Smooth Philtrum

– Thin Vermilion Border

• Other

– Maxillary Hypoplasia

– Cleft Plate

– Joint Anomalies

– Altered Palmar Creases

Moderate Alcohol Consumption

Alcohol

Consumed

Evidence of

Prenatal Effect

Alcohol

Normal

2 or more ounces ofabsolute alcohol

(n=16)3/16 (19%) 13/16 (81%)

1-2 ounces

absolute alcohol

(n=54)

6/54 (11%) 48/54 (89%)

Less than 1 ounceabsolute alcohol

(n=93)2/93 (2%) 91/93 (98%)

Metabolism of ETOH

ALDH

acetaldehyde

dehydrogenase

ADH

alcohol

dehydrogenase

Alcohol Acetaldehyde Acetate

NAD NADH NAD NADH

Genetic Polymorphisms: Impact on theRisk of FAS in Humans

• ADH unlike ALDH has a number of polymorphisms.

The isoenzymes which are encoded by thosepolymorphisms have differing ability to metabolize alcohol.

• Because ADH1B (previously referred to as ADH2)

encoded isoenzymes have significant differences in their

kinetic properties, it has been suggested that ADH1Balleles have a greater impact on the rate of alcoholmetabolism.

Genetic Polymorphisms: Impact onthe Risk of FAS in Humans

• ADH1B2 allele more common in control mothers thanin mothers of children with FAS from a mixed ancestrySouth African population.

(Viljoen et al.: Alcohol Clin Exp Res 25:1719, 2001)

• ADH1B3 allele more highly represented in controlmothers than in mothers of children with neurobehavioralabnormalities seen in association with prenatal alcoholexposure from two different studies involving US African-America populations.

(McCarver et al.: J Pharm Exp Ther 283: 1095, 1997)(Jacobson et al.: Alcohol Clin Exp Res 24:28A. 2000)

Genetic Polymorphisms: Impacton the Risk of FAS in Humans

Hypothesis: Because heightened metabolic activity of

ADH1B2 and ADH1B3 results in higher levels of thenoxious and unpleasant metabolic intermediate,acetaldehyde, women possessing these alleles drinkless and thereby do not attain as high a blood alcoholconcentration, reducing the risk of FAS.