Comprehensive survey of human genetic diseases

Medical GeneticsMedical Genetics

For Medical StudentFor Medical Student

Overview

Importance of Genetics to Medicine >12 million Americans with genetic disorders (GD)

80% of MR in America due to genetic component

2-3% background population risk for a major birth defect (BD)

15% overall miscarriage risk for any pregnancy

25-50% first trimester miscarriage risk

30-50% first trimester losses due to chromosome anomalies

>30% pediatric hospital admissions due to GD

GD affect all major systems, any age, any race, male or female

Importance of Genetics to Medicine

Changing focus of medicine:

primary care physicians vs specialists

prevention vs treatment

genetic causation for both rare and common diseases

Human Genome Project

designer drugs

Problem based approach taken in medical schools

Genetics as the link between basic research & clinical observation

Importance of Genetics to Medicine

Triple theme: genetic traits as they segregate through families

allows insights into health of the population

flow of info from DNA to RNA to protein links genetics to physiology

ethical issues linked to treatment, therapy options, research, decision-making and quality of life

Terms & Definitions

birth defect genetic disorder malformation deformation disruption sequence syndrome association morphology dysmorphology

variability heterogeneity pleiotrophy organogenesis morphogenesis hyperplasia hypoplasia dysplasia

Pedigree Symbols

See text for additional symbols:

normal male/female deceasedunknown sex stillbirthaffected male/female miscarriage (Sab)marriage/mating line termination of pregnancy

(Tab)illegitimacy line pregnancyconsanguineous mating consultandidentical/fraternal twins proband

Modes of Inheritance & Selected Examples

Heritable Birth Defects (HBD)

Single Gene Defects (SGD) Chromosomal Anomalies (CA) Multifactorial Inheritance (MF) Non-Classical Inheritance (NCI) Cancer Genetics (CG)

“Non-Heritable” Birth Defects (NHBD)

Environmental teratogensteratogen = any chemical,

biological or physical agent that increases the probability of a birth defect

Heritable Birth DefectsHeritable Birth Defects (HBD)(HBD)

Single Gene DefectsChromosomal AbnormalitiesMultifactorial DisordersNon-classical DisordersCancer Genetics

Single Gene DefectsSingle Gene Defects

Autosomal recessive Autosomal dominantX-linked recessive

X-linked dominant

HBD

Autosomal recessive (AR)

One trait, 2 allelesA = dominant normal allelea = recessive abnormal allele

Homozygous dominant = normal (AA)

Heterozygous dominant = normal, carrier (Aa)

Homozygous recessive = affected (aa)

HBD/SGD/AR

Autosomal recessive Carrier parents Normal parental

phenotype 75% chance for normal

offspring 25% chance for affected

offspring Males & females equally

affected “Inborn errors of

metabolism” Associated with specific

ethnic groups

HBD/SGD/AR

AR Pedigree

Pedigree symbols Proband “Horizontal” Equal numbers of

males and females Phenotypically normal

parents 25% recurrence risk

HBD/SGD/AR

AR Disorders PKU - phenylketonuria Galactosemia Homocystinuria Cystic fibrosis Tay-Sachs Sickle cell anemia

HBD/SGD/AR

AR Disorders & Ethnicity

Cystic fibrosis Tay-Sachs Sickle cell

anemia Thalassemia

Caucasians Ashkenazai Jews African Americans Mediterraneans

(ex:Greeks/Italians)

HBD/SGD/AR

Inborn Errors of MetabolismPhenylpyruvic acid 1Phenylalanine DOPA DOPA Quinone 2 3Tyrosine

P-hydroxyphenylpyruvic acid Homogentisic acid

4

Thyroid HormoneMaleylacetoacetic acid

1 = tyrosinase/albinism 3 = tyrosinase/albinism 2 = phenylalanine hydroxylase/PKU 4 = homogentisic acid

oxidase/alcaptonuria

HBD/SGD/AR

Inborn Errors of MetabolismInborn Errors of Metabolism General Characteristics

mental retardation hypopigmentation dislocated lens osteoporosis renal stones coarse facies and hair self-mutilation acute acidosis

unusual body odor unusual odor to urine family history of early death seizures overwhelming neonatal illness massive ketosis severe vomiting persistent hiccups

PhenylketonuriaPKU

PKU Major Clinical Features

MR Agitated behavior EEG abnormalities hyperactive reflexes muscular hypertonicity

inability to talk inability to walk tremors seizures

Tay-Sachs Disease

Tay-Sachs Major Clinical Features

psychomotor retardation psychomotor deterioration blindness apathy unresponsive hypotonia seizures EEG abnormalities megalencephaly absence of hexosaminidase A early death (2-4 years)

Cystic Fibrosis

CF Major Clinical Features defect of chloride ion transport increased exocrine mucous secretions salty-tasting skin persistent cough increased risk for pulmonary infections:

early: S. aures, H. influenzae, S. pneumonia late: P. aeruginosa

pneumonia poor weight gain despite excessive appetite bulky, foul-smelling stools clubbed fingers normal intelligence

CFTR Gene (Cystic Fibrosis Transmembrane Regulator)

250 kb encodes 1480 amino acid protein mutation first discovered in position 508 abnormal transport of chloride ions increased Cl- ions inside cell water enters cell by osmosis exterior of cell very viscous/mucous

Niemann-Pick Disease

NP Major Clinical Features

onset at 6 months foamy histiocytes in bone marrow failure to thrive mental retardation cherry-red macular spots respiratory infections hepatosplenomegaly absence of sphingomyelinase death by age 3

MucopolysaccharidosesMPS

MPS General Clinical Features

mental retardation frontal bossing hypertelorism prominent eyes gingival hypertrophy gapped teeth thick tongue storage of

mucopolysaccharides in body tissues

corneal clouding hepatosplenomegaly hand anomalies still joints congestive heart failure pneumonia kyphosis

Hurler’s SyndromeMPS Type 1

Hurler Major Clinical Features

growth retardation macrocephaly coarse facies full lips low nasal bridge corneal clouding abnormal teeth and

tongue

short, misshapen bones joint deformities thickening of coronary vessels hepatosplenomegaly hernias deafness

Sanfilippo SyndromeMPS Type 111

Sanfilippo Major Clinical Features

accelerated growth to 3 years growth retardation after 3 years mental deterioration mildly coarse facies variable hepatomegaly abnormal teeth mild cardiac anomalies

Scheie’s SyndromeMPS Type V

Scheie’s Major Clinical Features

normal intelligence corneal clouding joint limitation in hands aortic valvular defect body hirsutism hernias broad hands and feet

von Gierke’s Disease (Glycogen Storage Disorder Type I)

Von Gierke’s Major Clinical Features

absence of liver glucose–6-phosphatase

hypoglycemia short stature good prognosis accumulation of glycogen in liver and

kidneys

Ehlers-Danlos Syndrome

Ehlers-Danlos Major Clinical Features

hypermobile “lop” ears velvety skin fragile hyperextensive skin hyperextensible joints easy to bruise mitral valve prolapse collagen defect

Progeria

Progeria Major Clinical Features

alopecia thin skin hypoplasia of nails loss of subcutaneous fat skeletal hypoplasia,

dysplasia, degeneration

delayed eruption of teeth atherosclerosis mild elevation of serum

cholesterol premature aging normal intelligence

Spinal Muscular Atrophy Type I (Werdnig-Hoffman Disease)

SMA Type I Clinical Features

hypotonia weakness decreased or absent deep tendon

reflexes pulmonary infection respiratory failure rapid coarse to death at early age

Homocystinuria

Homocystinuria Clinical Features

abnormalities of skeletal system

genu valgum scoliosis kyphosis pectus excavatum

osteoporosis restricted joint mobility ectopia lentis (downward) thrombosis mental retardation

Single Gene DefectsSingle Gene Defects

Autosomal recessive Autosomal dominant

X-linked recessiveX-linked dominant

Autosomal dominant (AD)

One Trait, 2 allelesA = dominant abnormal allelea = recessive normal allele

Homozygous dominant = affected, often lethal (AA) Heterozygous dominant = affected (Aa)Homozygous recessive = normal (aa)

HBD/SGD/AD

Autosomal Dominant (AD) One parent affected (usually

heterozygous) Second parent normal 50% chance for affected

offspring 50% chance for normal offspring Males and females equally

affected Penetrance Variable expression

HBD/SGD/AD

AD Pedigree “Vertical”

Equal numbers of males and females affected

One parent genotypically & phenotypically normal

Other parent heterozygous affected

50% recurrence risk

HBD/SGD/AD

AD Disorders

Marfan’s Syndrome Huntington’s Chorea Osteogenesis imperfecta

Neurofibromatosis

Retinoblastoma Tuberous sclerosis Apert’s Syndrome Multiple polyposis of

colon

HBD/SGD/AD

Marfan Syndrome

Marfan Clinical Features

abnormalities of skeletal system

kyphoscoliosis pectus excavatum ectopia lentis

(upward) myopia

dilation of ascending aorta

mitral regurgitation dissecting aneurysm retinal detachment small lens

Crouzon’s Syndrome

Crouzon Major Clinical Features

shallow orbits premature craniosynostosis maxillary hypoplasia frontal bossing conductive hearing loss mental retardation (occasional) seizures (occasional)

Apert’s Syndrome

Apert Major Clinical Features

mental deficiency occasional normal intelligence irregular craniosynostosis (“Tower” skull) midfacial hypoplasia syndactyly (“mitten hand”) hypertelorism strabismus small nose maxillary hypoplasia

Treacher-Collin’s Syndrome

Treacher-Collin Clinical Features

mandibular hypoplasia lower lid colomboma malformation of auricles malar hypoplasia (with or

without cleft in zygomatic bone)

external ear canal defect conductive deafness cleft palate incompetent soft palate

Cherubism

Cherubism Major Clinical Features

tumor-like facial changes benign dysplasia of jaw bone serious dental anomalies

Neurofibromatosis

Neurofibromatosis Major Clinical Features

neurofibromas of skin, CNS, eye, stomach, liver, intestine, kidney, bladder, larynx

“café-au-lait” spots kyphoscoliosis feeble-minded

(occasional)

abnormal pigmentationof skin

iris hamartomas (Lischnodules)

tumorous partialgiantism (occasional)

Achondroplastic Dwarfism

Achondroplastic Dwarfism Major Clinical Features

megalocephaly short limbs low nasal bridge caudal narrowing of

spinal cord

lumbar lordosis skeletal anomalies mild hypotonia normal intelligence

Osteogenesis Imperfecta

Osteogenesis Imperfecta Major Clinical Features

“congenita” = severe form

multiple intrauterine fractures

“tarda” = later onset form

susceptibility to bone fracture

bone deformities joint laxity

short stature growth retardation kyphoscoliosis pectus excavatum yellow teeth thin skin blue sclerae

Holt-Oram Syndrome

Holt-Oram Major Clinical Features

defect of upper limb and shoulder girdle thumb hypoplasia or phocomelia asymmetry auricular septal defect cardiac arrythmia hypoplasia of distal blood vessels

Single Gene DefectsSingle Gene Defects

Autosomal recessive Autosomal dominant

X-linked recessiveX-linked dominant

X-linked recessive (XR)

One trait, 2 allelesA = dominant normal allelea = recessive abnormal allele

Must consider which parent has the abnormal gene when assessing risk

HBD/SGD/XR

X-linked recessive (XR)

Homozygous dominant = normal female (XAXA) Heterozygous dominant = normal female carrier (XAXa) Homozygous recessive = affected female (XaXa)

Hemizygous dominant = normal male (XAY) Hemizygous recessive = affected male (XaY)

HBD/SGD/XR

X-linked recessive (XR)

Heterozygous normal mother (carrier)

Hemizygous normal father50% risk for an affected male50% risk for a normal male

100% chance for normal female: 50% carrier female 50% homozygous normal female

Males and females NOT equally affected

HBD/SGD/XR

XR Pedigree

“Criss-cross” inheritance pattern

Female carriers risk affected sons

Female carriers risk carrier daughters

Often lethal to males

Transmission through normal females producing affected males

No male to male transmission

HBD/SGD/XR

XR Pedigree

“Criss-cross” inheritance pattern

Female carriers risk affected sons

Female carriers risk carrier daughters

Often lethal to males

Transmission through normal females producing affected males

No male to male transmission

HBD/SGD/XR

XR Disorders

Duchenne’s Muscular Dystrophy Hemophilia Hunter’s Syndrome Aarskog’s Syndrome Lesch-Nyhan Syndrome Pyruvate dehydrogenase deficiency

HBD/SGD/XR

Muscular Dystrophy

Muscular Dystrophy Major Clinical Features

hypotonia frequent stumbling difficulty climbing stairs difficulty getting up from floor pseudohypertrophy of calf muscles skeletal muscular weakness inability to walk between ages 5 and

15 absence of dystrophin protein death by age 20

Aarskog Syndrome

Aarskog Major Clinical Features

round face small nose brachydactyly slight to moderate

short stature

mild pectus excavatum prominent umbilicus shawl scrotum dull normal intelligence hypodontia

Lesch-Nyhan Syndrome

Lesch-Nyhan Major Clinical Features

spasticity choreoathetosis self-mutilation autistic behavior growth deficiency gout HGPRT deficiency (enzyme of purine

metabolism)

Hunter Syndrome(MPS Type II)

Hunter Major Clinical Features

coarse facies growth retardation stiff joints no corneal clouding neurological

deterioration severe mental

retardation

macrocephaly hepatosplenomegaly hernias progressive deafness abnormal dentition

Bruton’s Agammaglobulinemia

Bruton Major Clinical Features

normal appearance absence of serum antibodies risk of bacterial infection risk of pneumonia strong predisposition to rheumatoid

arthritis and to cancer

Single Gene DefectsSingle Gene Defects

Autosomal recessive Autosomal dominantX-linked recessive

X-linked dominant

X-linked dominant (XD)

One trait, 2 allelesA = dominant abnormal allelea = recessive normal allele

Must consider which parent has the abnormal gene when assessing risk

HBD/SGD/XD

X-linked dominant (XD)

Homozygous dominant = affected female (XAXA) Heterozygous dominant = affected female (XAXa)

Homozygous recessive = normal female (XaXa)

Hemizygous dominant = affected male (XAY) Hemizygous recessive = normal male (XaY)

HBD/SGD/XD

X-Linked Dominant (XD)

For heterozygous affected females:50% risk for affected son50% risk for affected daughter

For hemizygous affected males:100% risk for affected daughter0% risk for affected son

Males and females NOT equally affected

HBD/SGD/XD

Affected Father

Normal Mother

Affected Normal Affected Normal female male female male

XD Pedigree

Homozygous females often more severely affected than hemizygous males

Affected females risk affected sons and affected daughters

Affected males risk affected daughters

No male to male transmission

Difficult to distinguish from autosomal dominant

HBD/SGD/XD

XD Disorders

Vitamin D resistant rickets Browning of the enamel of the teeth Albright’s hereditary osteodystrophy Taybi Syndrome

HBD/SGD/XD

Vitamin D-resistant Rickets with hypophosphatemia

Resistant Rickets Major Clinical Features

bone deficiencies (“bowed” legs) dental anomalies decreased phosphate in serum short stature normal intelligence

Heritable Birth DefectsHeritable Birth Defects

Single Gene Defects Chromosomal Abnormalities

Multifactorial DisordersNon-classical DisordersCancer Genetics

Populations at Risk for Chromosome Errors spontaneous abortuses sexually ambiguous organisms infertile males or females newborns with multiple congenital anomalies mentally retarded mentally ill behaviorally disordered

specific cancers:Ataxia telangiectasia CMLBloom’s Syndrome Burkitt’s lymphomaFanconi’s anemia NeurofibromatosisXeroderma pigmentosum RetinoblastomaFamilial adenomatous polyposis Gardner’s Syndrome

Bruton’s agammaglobulinemia Wiskott-Aldrich Syndrome

Chromosome Preparation & Analysis

Obtain sample (eg: blood) Add WBC to chromosome media with mitogens (eg: PHA) Incubate at 37 degrees C (minimum of 3 days) Harvest after adding colchicine to arrest in metaphase Add fix (methanol:acetic acid) Prepare slides Treat with trypsin and Giemsa to induce G bands

Chromosome Banding

G bands C bands (centromere) Q bands (fluorescent equivalent to G) R bands (opposite pattern of G and Q) High resolution banding (>400 bands/haploid

set) FISH (fluorescent in situ hybridization) CGH (comparative genomic hybridization)

Chromosomes: A Review

Homologous pairs

Autosomes/sex chromosomes

Karyotype: arrange by size

Centromere position:metacentricsubmetacentric/p/qacrocentric/satellites/rDNA

G Banding

Nomenclature

HBD/CA

Normal Female: 46,XX

Normal Male: 46,XY

Acrocentric chromosome having a “bad hair day”

Note chromatids

“Fibrous” appearance

No bands apparent

Chromosomes: A Review

HBD/CA

Chromosomes: A Review

Idiogram:

standard for bands p and q arms centromere position bands numbered satellited chromosomes

HBD/CA

Chromosomes: A Review

chromosome #1 idiogram

largest, metacentric p and q arms with bands

and sub-bands

different band density shown

G-banded metaphase chromosome at lower left

HBD/CA

p

q

3

2

1

1

2

34

Chromosomal Anomalies

Trisomy: the presence of an extra chromosome Monosomy: the absence of a whole chromosome

Deletion: the absence of a part of a chromosome

Inversion: the 180° rotation of a part of a chromosome

Translocation: the breakage and rejoining of parts of

two, non-homologous chromosomes

HBD/CA

Chromosomal Abnormalities among Spontaneous Abortions

Type % (n=287)45,XO 23.7Other sex aneuploids 1.0Autosomal trisomies 49.8Triploids 13.2Tetraploids 4.2Rearrangements

balanced 0.3unbalanced 3.1

Other 4.5

Chromosomal Anomalies

Robertsonian translocation break break

21 21

14 14

14 21 14/21

HBD/CA

Chromosomal Anomalies

Possible Gametes for Trans

carrier 14, 21

14/21 14 21 14/21 21, 14/21

14, 14/21 Translocation carrier 14

21

HBD/CA

Chromosomal Anomalies

Carrier x Normal Offspring

14, 21 14, 21 normal 14/21 14,21 normal carrier

21, 14/21 14,21 translocation Down’s

14, 14/21 14,21 “trisomy” 14 (lethal)

14 14,21 monosomy 21 (lethal)

21 14,21 monosomy 14 (lethal)

HBD/CA

Chromosomal Anomalies

Theoretical risk (omitting lethal conditions):

1/3 normal

1/3 translocation carrier (normal)1/3 Down Syndrome

Actual risk for Down Syndrome:

1/10 if female is translocation carrier

1/20 if male is translocation carrier

HBD/CA

Chromosomal Anomalies

Abnormal number/kind of chromosomes

Autosomal anomalies Sex chromosome anomalies

HBD/CA

Autosomal Anomalies

General features:Mental retardation (MR)

Growth retardation (GR)Multiple congenital anomaliesPoor to moderate viabilityPrenatally diagnosableAssociated with spontaneous abortion

(Sab)

HBD/CA/Auto

Autosomal Anomalies

Trisomy 13 - Patau Syndrome Trisomy 18 - Edward Syndrome Trisomy 21 - Down Syndrome 5p- deletion - Cri-du-chat Syndrome

HBD/CA/Auto

Autosomal Abnormalities

Trisomy 21Down Syndrome

Down Syndrome 47,XY,+21

Nomenclature

47, XX, 21+ Female with Down Syndrome

47, XY, 21+Male with Down Syndrome

Trisomy 21 Major Clinical Features

mental retardation slanted palpebral

fissures epicanthal folds small, round, flat

face small mouth,

protruding tongue congenital heart

problems

Brushfield spots (iris) small, hypoplastic

ears simian creases hypotonia, lax joints,

hyperextensive

45, XY, D- G-, t(DqGq)

46, XY, D-, t(DqGq)

Trisomy 13Patau Syndrome

Patau Syndrome 47,XY,13+

Trisomy 13 Major Clinical Features

mental retardation growth retardation microcephaly cleft lip/palate small jaw

(micrognathia) deformed, low-set

ears

polydactyly congenital heart

defects rocker bottom feet seizures low birth weight

Trisomy 18Edward’ Syndrome

Edward’ Syndrome 47,XX,+18

Trisomy 18 Major Clinical Features

mental retardation growth retardation short neck cleft lip/palate dislocated

hips/abnormal pelvis deformed, low-set ears

hypertonia congenital heart

disease horseshoe kidneys hydronephrosis short sternum pyloric stenosis

Cri du chat Syndrome(5p-)

Cri du Chat 5p-

Cri du chat Major Clinical Features

distinctive cat-like cry profound developmental

retardation severe mental

retardation microcephaly hypotonia

hypertelorism congenital heart disease round, moon-shaped face large mouth, short philtrum low set ears hand and foot abnormalities

Sex ChromosomeAbnormalities

Sex Chromosome Anomalies

General features:Some growth retardation (GR)

Reproductive anomalies/problemsGood viabilityPrenatally diagnosableAssociated with spontaneous abortion

(Sab)

HBD/CA/Sex

Sex Chromosome Anomalies

Monosomy X: Turner’s Syndrome (45, X) Trisomy X: Triplo-X Syndrome (47, XXX) Trisomy (47, XXY): Klinefelter’s

Syndrome Trisomy (47, XYY): XYY Syndrome

HBD/CA/Sex

Turner’s Syndrome

Turner’s Syndrome 45,X

Turner’s Syndrome Major Clinical Features

female phenotype short (less than 5 feet) primary amenorrhea low estrogen levels maldevelopment of the

ovaries sterility

webbing of the skin of the neck

wide-spaced nipples edema at birth cardiovascular

problems

Klinefelter’s Syndrome

Klinefelter’s Syndrome 47,XXY

Klinefelter’s Syndrome Major Clinical Features

small testes aspermia (little to no sperm production) gynecomastia long limbs large hands & feet retardation in some fertility in some social limitations in some

Chromosome Instability Syndromes

Bloom’s Syndrome

Bloom’s Syndrome Major Clinical Features

prenatal onset of growth deficiency

short stature malar hypoplasia telangiectatic

erythema of the face mild microcephaly

mild mental deficiency (occasional)

sensitivity to light increased rate of

chromosome breakage

predisposition to malignancy

Fanconi’s Anemia

Fanconi’s Anemia Major Clinical Features

short stature radial hypoplasia hyperpigmentation pancytopenia absent thumbs

progressive muscular wasting

hypoplastic and/or malformed kidneys

congenital dislocation of the hip

Heritable Birth DefectsHeritable Birth Defects

Single Gene DefectsChromosomal Abnormalities

Multifactorial DisordersNon-classical DisordersCancer Genetics

Risk to Relatives for Same Malformation as Index Case

Malformation Risk (population risk compared to degree of relationship)

Pop First Second Third

Cleft lip/palate 1/1000 35x 7x 3xCongenital dislocation/hip 1/1000 40x 4x 1.5xPyloric stenosis 1/1000 20x 5x 2xClubfoot 1/1000 20x 5x 2xAnencephaly/spina bifida 1/500 8x 2x

Multifactorial Inheritance

One trait

Multifactorial: many “factors” governing 1 trait genes plus environment

Polygenic: many loci more than 2 alleles/locus

HBD/MF

Multifactorial Inheritance

environment

PotentialActual

GenotypePhenotype(genes) (appearance)

HBD/MF

Multifactorial Inheritance

anencephaly atopic allergies cleft lip/palate club foot congenital heart disease congential hip dysplasia congenital scoliosis diabetes mellitus epilepsy

hydrocephalus hyperlipidemias manic depressive psychoses non-specific MR NTD presenile dementias pyloric stenosis schizophrenia urinary tract malformations

HBD/MF

Cleft lip/Palate

Cleft lip/Palate Major Clinical Features

failure of upper lip fusion failure of closure of palate defects in tooth development mild ocular hypertelorism (in some) normal intelligence potential for poor speech potential otitis media

Midline Dysplasia

Midline Dysplasia Major Clinical Features

ocular hypertelorism lateral displacement of inner canthi widow’s peak failure of apposition of eyes broad nasal bridge median cleft lip potential bifid nostrils

Neural Tube Defects (NTD)

Neural Tube Defects

anencephaly myelomeningocoele meningocoele encephalocoele

Anencephaly Major Clinical Features

partial or complete absence of calvarium and cranial vault

missing cerebral hemispheres incompatible with postnatal life

Encephalocoele Major Clinical Features

herniation of brain and meninges through a defect in the skull

Spina Bifida Major Clinical Features

defect in spinal cord with sac-like protrusion open or closed wide variability dependent upon location

along spine prognosis based on tissue in sac:

Myelomeningocoele: includes meninges, spinal cord, and nerves

Meningocoele: includes meninges and is covered

Infant of Diabetic Mother

Infant of Diabetic Mother Major Clinical Features

increased intrauterine growth macrosomia (birth weight > 10 lbs.) increased risk for congenital malformations:

caudal regression sacral agenesis hypoplastic femurs renal anomalies cardiac anomalies NTD

Hypospadias Glandis

Hypospadias Glandis Major Clinical Features

opening of the male urethra on the undersurface of the penis

cutaneous or fibrous chordee complications may include:

microphallus cryptorchidism inguinal hernia bifid scrotum

Exstrophy of Bladder(ectopia vesicae)

Exstrophy of Bladder Major Clinical Features

increased MSAFP levels breakdown in cloacal membrane displacement of the bladder exposure of posterior bladder wall increased risk of infection intestinal epithelium between hemibladders phallic separation with epispadias rudimentary hindgut with imperforate anus

Gastroschisis

Gastroschisis Major Clinical Features

increased MSAFP levels intact umbilicus fissure in abdominal wall herniation of abdominal region no sac covering the anomaly increased risk of infection low birth weight small abdominal cavity

Omphalocoele

Omphalocoele Major Clinical Features

increased MSAFP levels herniation of abdominal region including

umbilicus sac covering the anomaly increased risk of infection low birth weight small abdominal cavity

Sirenomelia

Sirenomelia Major Clinical Features

alteration in early vascular development

absent or incomplete development of caudal structures

single lower extremity with posterior alignment of knees and feet

vertebral defects imperforate anus absence of rectum absence of internal &

external genitalia renal agenesis absence of bladder absence of sacrum

Cystic Hygroma

Cystic Hygroma Major Clinical Features

fluid filled, rapidly growing sac or bursa lymphatic in origin located primarily in neck; may be in thorax benign and asymptomatic complications include hemorrhage, infection,

airway obstruction

Rubenstein-Taybi Syndrome

Rubenstein-Taybi Syndrome Major Clinical Features

short stature mental retardation EEG abnormality epicanthal folds hypoplastic maxilla

with narrow palate

low-set/malformed ears hand and foot

anomalies cryptorchidism cardiac murmurs renal anomalies small head

Cornelia de Lange Syndrome

Cornelia de Lange Syndrome Major Clinical Features

short stature mental retardation hypertonicity low-pitched, weak,

growling cry microbrachycephaly bushy eyebrows

small nose high arched palate micrognathia hirsutism hypoplastic nipples and

umbilicus hand and foot

anomalies

Amniotic Band Syndrome

Amniotic Band Syndrome Major Clinical Features

3 weeks: anencephaly facial distortion facial clefting eye defects encephalocoele

5 weeks: cleft lip choanal atresia limb reduction abdominal wall defects thoracic wall defects

7 weeks: cleft palate ear deformation craniostenosis amputation hypoplasia dislocation of hip

Heritable Birth DefectsHeritable Birth Defects

Single Gene Defects Chromosomal Abnormalities

Multifactorial Disorders Non-classical Disorders

Cancer Genetics

Non-Classical Inheritance

Uniparental Disomy (UPD)Trinucleotide Repeat Disorders

(TNR)Mitochondrial/Maternal Inheritance

Uniparental Disomy(UPD)

Uniparental disomy (UPD)

Uniparental disomy: both homologues come from the same parent, none from the other

eg: 2 #7 chromosomes from mom, none from dad

Isodisomy vs heterodisomy

HBD/NCI/UPD

Uniparental disomy (UPD)

female male

7A 7B 7C 7D

Isodisomy 7A 7A

Heterodisomy 7A 7B

HBD/NCI/UPD

Uniparental disomy (UPD)

Prader-Willi and Angelman Syndromes etiologies: autosomal recessive

15q11-13 deletion: PWS results from paternal deletion AS results from maternal deletion

UPD: PWS results from 2 maternal #15 chromosomes AS results from 2 paternal #15 chromosomes

HBD/NCI/UPD

Uniparental disomy (UPD)

Why does it make a difference if an individual has two maternal homologues or two paternal homologues or one homologue fromm each?

HBD/NCI/UPD

Uniparental disomy (UPD)

Genetic Imprinting:

“…modifications of genetic material that take place depending upon whether the information is derived from the mother or the father…” Judith Hall (1990)

chromosomes are “imprinted” by the parent

HBD/NCI/UPD

Uniparental disomy (UPD)

Early mouse experiments

Enucleate an egg cell leaving only cytoplasm

Add 2 maternal genomes (diploid female cell)

OR

Add 2 paternal genomes (diploid male cell)

HBD/NCI/UPD

Control 2 maternal genomes

2 paternal genomes

YS

E

EEM

Prader-Willi Syndrome(Chromosomal)

Prader-Willi Major Clinical Features

mental retardation obesity dental caries macrophagy skin lesions

small hands/feet cryptorchidism small genitalia 15q11-q13 deletion

(70% paternal)

Angelman Syndrome(Chromosomal)

Angelman Major Clinical Features

severe to profound mental retardation inappropriate, excessive laughter epilepsy aphasia 15q11-q13 deletion (80% maternal)

Trinucleotide Repeat(TNR) Disorders

Trinucleotide Repeat Disorders

TNR: repeat of 3 (tri) nucleotides from

30 to 100s of copies (eg: CGGCGGCGGCGGCGGCGG)

premutation: 50 - 230 repeats full mutation: > 230 repeats

HBD/NCI/TNR

Trinucleotide Repeat Disorders

Dynamic mutations: “…the capability of a trinucleotide to

expand into multiple copies within one generation… the ability to increase in copy number over several generations…”

heritable, unstable DNA

HBD/NCI/TNR

Trinucleotide Repeat Disorders

Anticipation: the observation that a disease becomes

progressively worse and demonstrates earlier onset in subsequent generations;

maybe due to or related to dynamic mutations and TNR

HBD/NCI/TNR

Trinucleotide Repeat Disorders

Huntington’s Disease Fragile X Syndrome Myotonic dystrophy Kennedy Disease Spinocerebellar ataxia Machado-Joseph disease

HBD/NCI/TNR

Myotonic Dystrophy(AD)

Myotonic Dystrophy Major Clinical Features

Fetus: oligohydramnios decreased movement impaired fetal swallowing

Newborn: profound neonatal hypotonia severe feeding problems

Adult: myotonia muscle weakness and wasting cataracts GI, cardiac, endocrine problems 50-100 TNR = affected

Huntington’s Chorea(AD)

Huntington’s Chorea Major Clinical Features

chorea dementia clumsy gait indistinct speech

emotional instability paranoia progressive

deterioration late onset of symptoms

Fragile X Syndrome(Martin-Bell Syndrome)

(Chromosomal)

Fragile X Major Clinical Features

Males: large loppy ears prominent forehead

and jaw large testes educable to severe

MR 20% unaffected,

transmitting males

Females: slow learners mild MR shy some affected carriers

Fragile X Syndrome

Fragile X

Mitochondrial/Maternal Inheritance

Mitochondrial Inheritance

Mitochondria: semi-autonomous, circular, naked DNA (~prokaryotic

chromosome) encodes tRNA genes, rRNA genes, some structural genes

(mRNA) important in respiration, production of ATP critical to tissues with high demand for ATP “maternally” inherited random segregation during cell division = heteroplasmy higher mutation rate than nuclear DNA

HBD/NCI/Mito

Mitochondrial Inheritance

Heteroplasmy = different % of normal & abnormal mitochondria in single cells or tissues

and or and

HBD/NCI/Mito

x x x x x x o o o o o o o o o o o o

O o o

x x x xo o o o o

x x o o o o o o o

x o o o o o o o o o

x x x x xo o o

Mitochondrial Inheritance

Disease phenotype dependent upon:

gene(s) involved type of mutation (missense/nonsense/deletion) % normal vs abnormal mitochondria tissue involved

HBD/NCI/Mito

Mitochondrial Disorders

Diabetes with sensorineural deafness HOCM (hypertrophic cardiomyopathy with myopathy)

Leber’s Hereditary Optic Neuropathy MELAS (encephalopathy, lactic acidosis, stroke-like episodes)

MERRF (myoclonic epilepsy, mito myopathy with ragged-red fibers)

HBD/NCI/MD

Myoclonic Encephalopathy with Ragged Red Fibers

(MERRF)

MERRF Major Clinical Features

ataxia epilepsy hypotonia muscle weakness lactic acidemia ragged red fibers seen in muscle biopsy abnormal energy metabolism in muscles

Heritable Birth DefectsHeritable Birth Defects

Single Gene DefectsChromosomal AbnormalitiesMultifactorial DisordersNon-classical Disorders

Cancer Genetics

Basic Definitions of Terms

Proto-oncogene = a normal gene which controls cell division (“speeds up”)

Oncogene = a mutated or abnormal proto-oncogene which induces cell division at the wrong time, place or rate

Tumor Suppressor (TS) gene = a normal gene which controls cell division (“slows down”)

Mutated TS gene = an abnormal gene which fails to stop cell division at the appropriate time or place

General Classes of Cancer

Breast Colorectal Leukemia Lymphoma Skin

Ovarian Pancreatic Prostate Testicular Uterine

HBD/CG

Specific Cancers

CML, AML (leukemias) Burkitt’s, Hodgkin’s, non-Hodgkin’s (lymphomas) Retinoblastoma (retina) LiFraumeni Syndrome

Retinoblastoma(AD)

Retinoblastoma Major Clinical Features

malignant tumor of the retina onset at birth/early childhood bilateral cases are hereditary poor vision or blindness painful, red eye 13q14 deletion

Chronic Myelogenous Leukemia (CML)

CML Major Clinical Features

hyperplastic bone marrow granulocytic leukocytosis weakness due to anemia pain due to splenomegaly weight loss Philadelphia chromosome = 9/22 translocation 9q34 abl gene + 22q11 bcr gene hybrid gene forms new hybrid protein

46,XX,Ph1+

Non-Heritable Birth DefectsNon-Heritable Birth Defects

Environmental Teratogens

“Non-Heritable” Birth Defects (NHBD)

teratogen = any chemical, biological or physical agent that increases the probability of a birth defect

“Non-Heritable” Birth Defects

drugs (OTC/illegal)

chemicals X-rays oxygen

deprivation toxins

infections accidents/injuries alcohol nicotine caffeine poisons

Fetal Alcohol Syndrome

Fetal Alcohol Syndrome Major Clinical Features

prenatal growth deficiency

thin upper lips mental retardation visual impairment hearing loss low nasal bridge epicanthal folds

indistinct philtrum short palpebral fissures flat midface short nose micrognathia malformations of the

heart, kidney, eye, brain, ear, skeleton

Fetal Rubella Effects

Fetal Rubella Effects Major Clinical Features

deafness cataracts patent ductus arteriosus mental retardation glaucoma

septal defects thrombocytopenia hepatosplenomegaly interstitial pneumonia

Fetal Hydantoin Syndrome

Fetal Hydantoin Major Clinical Features

mental retardation distal phalangeal hypoplasia facial clefts cardiac anomalies

Fetal Warfarin Effects

Fetal Warfarin Effects Major Clinical Features

nasal hypoplasia depressed nasal bridge skeletal stippling mild hypoplasia of nails short fingers low birth weight mental retardation

Hyperthermia

Hyperthermia Major Clinical Features

defects dependent upon time of exposure

mental deficiency hypertonicity neurogenic contractures seizures hormone deficiency

microphthalmia micrognathia midfacial hypoplasia external ear anomalies cleft lip/palate microcephaly

Pierre-Robin Syndrome

Pierre-Robin Syndrome Major Clinical Features

micrognathia glossoptosis cleft soft palate early mandibular hypoplasia upper respiratory obstruction failure to thrive

Potter’s Syndrome

Potter’s Syndrome Major Clinical Features

renal agenesis oligohydramnios multiple malformations growth deficiency fetal compression in utero altered facies limb positioning defects

Amelia/Phocomelia

Amelia/Phocomelia Major Clinical Features

Amelia: complete absence of limb/limbs

Phocomelia: microbrachycephaly mild to severe mental deficiency growth deficiency cleft lip and/or cleft palate sparse hair cryptorchidism

Radiation Exposure

Radiation Exposure Major Clinical Features

defects dependent upon dosage and time high dose:

lethal early in pregnancy multiple malformations if later in pregnancy

2-10 rads: very slight increased risk for birth defects if

between 2 and 4 weeks gestation 2 rads:

very low increased risk

Caffeine/Tobacco(“stimulants”)

Caffeine/Tobacco Major Clinical Features

caffeine: potential co-teratogen with tobacco

tobacco: miscarriages reduced birth weight due to vasoconstriction potential co-teratogen with caffeine