Comprehensive survey of human genetic diseases

Medical GeneticsMedical Genetics
For Medical StudentFor Medical Student

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

 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

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 deceased
unknown sex stillbirth
affected male/female miscarriage (Sab)
marriage/mating line termination of pregnancy (Tab)
illegitimacy line pregnancy
consanguineous mating consultand
identical/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 teratogens
teratogen = any chemical, biological
or physical agent that increases the
probability of a birth defect

Heritable Birth DefectsHeritable Birth Defects
(HBD)(HBD)
 Single Gene Defects
Chromosomal Abnormalities
Multifactorial Disorders
Non-classical Disorders
Cancer Genetics

Single Gene DefectsSingle Gene Defects
 Autosomal recessive
Autosomal dominant
X-linked recessive
X-linked dominant
HBD

Autosomal recessive (AR)
 One trait, 2 alleles
A = dominant normal allele
a = 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 Metabolism
Phenylpyruvic acid
1
Phenylalanine DOPA DOPA Quinone
2
3
Tyrosine
P-hydroxyphenylpyruvic acid Homogentisic acid
4
Thyroid Hormone
Maleylacetoacetic 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

PKU Major Clinical
Features
 MR
 Agitated behavior
 EEG abnormalities
 hyperactive reflexes
 muscular hypertonicity
 inability to talk
 inability to walk
 tremors
 seizures

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)

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

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

MPS General Clinical
Features
 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 Syndrome
MPS 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
 hernias
 deafness

Sanfilippo Syndrome
MPS 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 Syndrome
MPS 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 Major Clinical
Features

hypermobile “lop” ears

velvety skin

fragile hyperextensive skin

hyperextensible joints

easy to bruise

mitral valve prolapse

collagen defect

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 Clinical
Features
 abnormalities of
skeletal system
 genu valgum
 scoliosis
 kyphosis
 pectus excavatum
 osteoporosis
 restricted joint mobility
 ectopia lentis (downward)
 thrombosis

Autosomal recessive
 Autosomal dominant
X-linked recessive
X-linked dominant

Autosomal dominant (AD)
 One Trait, 2 alleles
A = dominant abnormal allele
a = 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 Clinical Features
 abnormalities of
skeletal system
 kyphoscoliosis
 ectopia lentis (upward)
 myopia
 dilation of ascending aorta
 mitral regurgitation
 dissecting aneurysm
 retinal detachment
 small lens

Crouzon Major Clinical
Features

shallow orbits

premature craniosynostosis

maxillary hypoplasia

frontal bossing

conductive hearing loss

mental retardation (occasional)

seizures (occasional)

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 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 Major Clinical
Features

tumor-like facial changes

benign dysplasia of jaw bone

serious dental anomalies

Neurofibromatosis
Major Clinical Features
 neurofibromas of skin,
CNS, eye, stomach, liver,
intestine, kidney,
bladder, larynx
 “café-au-lait” spots
 kyphoscoliosis
 feeble-minded
(occasional)
 abnormal pigmentation
of skin
 iris hamartomas (Lisch
nodules)
 tumorous partial
giantism (occasional)

Achondroplastic Dwarfism
 megalocephaly
 short limbs
 caudal narrowing of
spinal cord
 lumbar lordosis
 skeletal anomalies
 mild hypotonia

Osteogenesis Imperfecta
 “congenita” = severe form
 multiple intrauterine
fractures
 “tarda” = later onset form
 susceptibility to bone
fracture
 bone deformities
 joint laxity
 short stature
 kyphoscoliosis
 yellow teeth
 thin skin
 blue sclerae

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

Autosomal recessive
Autosomal dominant
 X-linked recessive
X-linked dominant

X-linked recessive (XR)

One trait, 2 alleles
A = dominant normal allele
a = recessive abnormal allele

Must consider which parent has the
abnormal gene when assessing risk
HBD/SGD/XR

 Homozygous dominant = normal female (XA
XA
)
 Heterozygous dominant = normal female carrier (XA
Xa
)
 Homozygous recessive = affected female (Xa
Xa
)
 Hemizygous dominant = normal male (XA
Y)
 Hemizygous recessive = affected male (Xa
Y)
HBD/SGD/XR

 Heterozygous normal mother
(carrier)
 Hemizygous normal father
50% risk for an affected male
50% 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 Disorders

Duchenne’s Muscular Dystrophy

Hemophilia

Hunter’s Syndrome

Aarskog’s Syndrome

Lesch-Nyhan Syndrome

Pyruvate dehydrogenase deficiency
HBD/SGD/XR

Muscular Dystrophy
 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 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
 spasticity
 choreoathetosis
 self-mutilation
 autistic behavior
 growth deficiency
 gout
 HGPRT deficiency (enzyme of purine
metabolism)

Hunter Major Clinical
Features
 coarse facies
 stiff joints
 no corneal clouding
 neurological deterioration
 severe mental retardation
 macrocephaly
 hernias
 progressive deafness
 abnormal dentition

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

Autosomal recessive
Autosomal dominant
X-linked recessive
 X-linked dominant

X-linked dominant (XD)
 One trait, 2 alleles
A = dominant abnormal allele
a = 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 (XA
XA
)
 Heterozygous dominant = affected female (XA
Xa
)
 Homozygous recessive = normal female (Xa
Xa
)
 Hemizygous dominant = affected male (XA
Y)
 Hemizygous recessive = normal male (Xa
Y)
HBD/SGD/XD

X-Linked Dominant (XD)
 For heterozygous affected females:
50% risk for affected son
50% risk for affected daughter
 For hemizygous affected males:
100% risk for affected daughter
0% 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
 bone deficiencies (“bowed” legs)
 dental anomalies
 decreased phosphate in serum
 short stature

Single Gene Defects
 Chromosomal Abnormalities
Cancer 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 CML
Bloom’s Syndrome Burkitt’s lymphoma
Fanconi’s anemia Neurofibromatosis
Xeroderma pigmentosum Retinoblastoma
Familial 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:
metacentric
submetacentric/p/q
acrocentric/satellites/rDNA
 G Banding
 Nomenclature
HBD/CA

 Acrocentric chromosome
having a “bad hair day”
 Note chromatids
 “Fibrous” appearance
 No bands apparent
HBD/CA

 Idiogram:
 standard for bands
 p and q arms
 centromere position
 bands numbered
 satellited chromosomes
HBD/CA

 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
3
4

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

among Spontaneous Abortions
Type % (n=287)
45,XO 23.7
Other sex aneuploids 1.0
Autosomal trisomies 49.8
Triploids 13.2
Tetraploids 4.2
Rearrangements
balanced 0.3
unbalanced 3.1
Other 4.5


Robertsonian translocation
break break
21 21
14 14
HBD/CA

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

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

 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

 Abnormal number/kind of chromosomes
 Autosomal anomalies
 Sex chromosome anomalies
HBD/CA

Autosomal Anomalies
General features:
Mental retardation (MR)
Growth retardation (GR)
Multiple congenital anomalies
Poor to moderate viability
Prenatally diagnosable
Associated 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

Nomenclature
47, XX, 21+
Female with Down Syndrome
47, XY, 21+
Male with Down Syndrome

Trisomy 21
 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

Trisomy 13
 microcephaly
 cleft lip/palate
 small jaw
(micrognathia)
 deformed, low-set ears
 polydactyly
 congenital heart defects
 rocker bottom feet
 seizures
 low birth weight

Trisomy 18
 short neck
 dislocated
hips/abnormal pelvis
 deformed, low-set ears
 hypertonia
 congenital heart
disease
 horseshoe kidneys
 hydronephrosis
 short sternum
 pyloric stenosis

Cri du chat
 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 Chromosome Anomalies
 General features:
Some growth retardation (GR)
Reproductive anomalies/problems
Good viability
Prenatally diagnosable
Associated 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
 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
47,XXY

Klinefelter’s Syndrome
 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
 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
 short stature
 radial hypoplasia
 hyperpigmentation
 pancytopenia
 absent thumbs
 progressive muscular
wasting
 hypoplastic and/or
malformed kidneys
 congenital dislocation
of the hip

Single Gene Defects
 Multifactorial Disorders
Cancer 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 3x
Congenital dislocation/hip 1/1000 40x 4x 1.5x
Pyloric stenosis 1/1000 20x 5x 2x
Clubfoot 1/1000 20x 5x 2x
Anencephaly/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

environment
Potential Actual
Genotype Phenotype
(genes) (appearance)
HBD/MF

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

Midline Dysplasia
 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
 anencephaly
 myelomeningocoele
 meningocoele
 encephalocoele

Anencephaly
 partial or complete absence of calvarium and
cranial vault
 missing cerebral hemispheres
 incompatible with postnatal life

Encephalocoele
 herniation of brain and meninges through a
defect in the skull

Spina Bifida
 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
 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
 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
 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
 intact umbilicus
 fissure in abdominal wall
 herniation of abdominal region
 no sac covering the anomaly
 small abdominal cavity

Omphalocoele
 herniation of abdominal region including
umbilicus
 sac covering the anomaly
 small abdominal cavity

Sirenomelia
 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
 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
 short stature
 EEG abnormality
 hypoplastic maxilla
with narrow palate
 low-set/malformed ears
 hand and foot anomalies
 cryptorchidism
 cardiac murmurs
 renal anomalies
 small head

Cornelia de Lange Syndrome
 short stature
 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
 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

Single Gene Defects
 Non-classical Disorders
Cancer Genetics

Non-Classical Inheritance
Uniparental Disomy (UPD)
Trinucleotide Repeat Disorders
(TNR)
Mitochondrial/Maternal Inheritance

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

female male
7A 7B 7C 7D
Isodisomy 7A 7A
Heterodisomy 7A 7B
HBD/NCI/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

 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

 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

 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
 obesity
 dental caries
 macrophagy
 skin lesions
 small hands/feet
 cryptorchidism
 small genitalia
 15q11-q13 deletion
(70% paternal)

Angelman Syndrome
(Chromosomal)

Angelman
 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

 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

 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

 Huntington’s Disease
 Fragile X Syndrome
 Myotonic dystrophy
 Kennedy Disease
 Spinocerebellar ataxia
 Machado-Joseph disease
HBD/NCI/TNR

Myotonic Dystrophy
 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
 chorea
 dementia
 clumsy gait
 indistinct speech
 emotional instability
 paranoia
 progressive deterioration
 late onset of symptoms

Fragile X Syndrome
(Martin-Bell Syndrome)
(Chromosomal)

Fragile X
 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

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


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 x
o 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 x
o o o

 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

Single Gene Defects
 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

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

Non-Heritable BirthNon-Heritable Birth
DefectsDefects
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
 prenatal growth deficiency
 thin upper lips
 visual impairment
 hearing loss
 indistinct philtrum
 short palpebral fissures
 flat midface
 short nose
 micrognathia
 malformations of the
heart, kidney, eye,
brain, ear, skeleton

Fetal Rubella Effects
 deafness
 cataracts
 patent ductus arteriosus
 glaucoma
 septal defects
 thrombocytopenia
 interstitial pneumonia

Fetal Hydantoin

mental retardation

distal phalangeal hypoplasia

facial clefts

cardiac anomalies

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

Hyperthermia
 defects dependent upon
time of exposure
 mental deficiency
 hypertonicity
 neurogenic contractures
 seizures
 hormone deficiency
 microphthalmia
 micrognathia
 midfacial hypoplasia
 external ear anomalies
 microcephaly

Pierre-Robin Syndrome
 micrognathia
 glossoptosis
 cleft soft palate
 early mandibular hypoplasia
 upper respiratory obstruction
 failure to thrive

Potter’s Syndrome
 renal agenesis
 oligohydramnios
 multiple malformations
 fetal compression in utero
 altered facies
 limb positioning defects

Amelia/Phocomelia
 Amelia:
 complete absence of limb/limbs
 Phocomelia:
 microbrachycephaly
 mild to severe mental deficiency
 cleft lip and/or cleft palate
 sparse hair
 cryptorchidism

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

Comprehensive survey of human genetic diseases

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