comprehensive survey of human genetic diseases
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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
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