GENETIC DISORDER FEATURES
Slanted palpebral fissures
Simian crease
Hypotonia
Trisomy 21
Poor Moro reflex
Down Syndrome
Mental retardation
Epicampal folds
Congenital heart defects 44% die
Punching fists
Index finger and little finger
overlapping 3rd and 4th fingers
Trisomy 18
Polyhydramios
Edward Syndrome
Microencephaly
Cleft lip/palate
Hypertonia
Polycystic kidney
Polydactyly
Cleft lip/palate
Midfacial (forebrain) abn.
Holoprosencephaly
Trisomy 13
Micrognathia
Patau Syndrome
Rocker bottom feet
Apneic episodes
Mental Retardation
Feeding Problems
80% die in first month
Large head, small body
Cardiac defects
Pre-eclampsia
Hydatiform placenta
Intrauterine growth retardation
Syndactyly
Triploidy
Simian creases
Skeletal asymmetry
Large cystic placentas with partial
molar changes (2 M, 1F)
Small underdeveloped placenta (2F,
1M)
99% lost early in preg
Cleft/soft palate
speech and feeding problems
velopharyngeal incompetence; VPI
Velocardiofacial
Hypocalcemia
syndrome VCFS
immunodeficiency (due to absent or
DiGeorge, Catch-22
small thymus) thymic aplasia
22q -deletion
hypoparathyroidism
learning disability
Conotruncal cardiac defect
Cri-du-Chat Syndrome Cat-like cry (abn laryngeal develp)
INCIDENCE
ETIOLOGY
RECURRC
1:600
80% F<35
5% M
MUT TRAITS
INHERITANCE
 3 copies of all or a
part of chromos 21
 95 %Nondisjunction
Chromosomal
 1% Mosaicism
 4% Translocation
 3 copies of entire
chromosome 18
 Nondisjunction
 Mosaicism
 Translocation
Chromosomal
 3 copies of entire
chromosome 13
 Nondisjunction
 Mosaicism
 Translocation
Chromosomal
CARRIERS
TESTING
rr 1%
0.3/1000
3:1 F:M
rr <1%
0.2/1000
rr 1%
 Genomic Imprinting
2%
rr 1%
 69 Chromosomes
w/double from 1
parent
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Mixoploidy
Mosaicism
70-90% paternally
55% dispermy
60% 69 XXY
rest XXX
66% double fert
24% diploid sperm
10% diploid egg
Chromosomal
 Microdeletion
 Chromosome 22q11  95% have a deletion Chromosomal
deletion
of a small portion of
 94% are de novo
deletion
 Chromosome 5p
 Microdeletion
Chromosomal
FISH
w/syndrome
specific probe
GENETIC DISORDER FEATURES
XYY Syndrome
XXY Klinefelter
Syndrome
45XO Turner
Syndrome
Hemophilia A
Hemophilia B
Christmas Disease
Duchenne Muscular
Dystrophy (DMD)
Becker Muscular
Dystrophy (BMD)
Microcephaly
Intrauterine growth retardation
Slow growth, hypotonia
Mental retardation
Hypertelorism, strabismus,
epicampal folds
Downward slanting palpebral fiss.
Phenotypic normal male
Tall thin stature
Muscle weakness
Poor fine motor coordination
Dull mentality, Low IQ
Fertile
Severe nodulocystic acne
Facial asymmetry w/large teeth,
long ears, prominent glabella
Most common cause of
Hypogonadism and Infertility M
Testosterone insufficiency
Late onset of speech
Behavior problems
Long limbs w/big upper/lower body
Gynecomastia 40%
Intention Tremor 20-50%
Tall thin stature (obese w/o test)
Hyalinization/fibrosis of semi tubule
Phenotypic female
Small stature
Hearing loss
Webbed neck – pterygium colli
Gonadal dysgenesis
Transient congenital Lyphedema
w/puffy hands and feet
Cubitus valgus
Cardiac anomalies
More males than females
Coagulation deficiency
INCIDENCE
ETIOLOGY
RECURRC
INHERITANCE
CARRIERS
TESTING
deletion (short arm)
 Majority de novo
 10% translocation
1:840
 Extra Y
Chromosome
 47 XY
Chromosomal
1:500
 Extra X
Chromosome
 75% XXY
 22% XXY/XY
mosaic
 few XXYY/ XXXY
Chromosomal
1:5000
 Paternal set of
chromosomes
missing
 45X
1/10,000
1/5000 M
More males than females
Coagulation deficiency
Young boys
Proximal muscle weakness
Gower’s maneuver
Large calves
High blood creatine kinase
Milder severity
Weakness develops later
Survive to mid-adulthood
MUT TRAITS
1:4000 M
 Mosaicism
 45X/46XX mosaics
 Partial deletion of
Chromosomal
one X chromosome
 45X/46XY
gonadoblastoma
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X Chromosome
 Large inversion
Factor VIII mutation  Insertion of LINE
X Chromosome
Xq27.1
Factor IX mutation
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X Chromosome
Xq21
Dystrophin gene
Largest gene
 X Chromosome
 Dystrophin gene
Treat
w/testosterone
X-Linked Recessive
Locus heterogeneity
All daughters
are carriers
X-Linked Recessive
Locus heterogeneity
 >90% deletions
 Frame shift mut
 Premature
termination
X-Linked Recessive
Allelic heterogeneity
 >90% deletions
 In-frame deletions
X-Linked Recessive
Allelic heterogeneity
F: high blood
protein
GENETIC DISORDER FEATURES
INCIDENCE
ETIOLOGY
RECURRC
Neurological syndrome
Nystagmus
Severe spastic quadriparesis
Cognitive impairment
Pelizaeus-Merzbacher
Ataxia
Disease (PMD)
Leukodystrophy
Apoptosis of oligodendrocytes
Mild: demyelinating peripheral
neuropathy
Phenotypic females
Large breasts
Testicular
Internal testes
Feminization (TFM)
Lack of internal female genitalia
Androgen Insensitivity
Lack of menstruation, pubic, axillary
hair, infertile
Spinal and Bulbar
Muscular Atrophy
(SBMA) Kennedy Dx
 X Chromosome
 Xq21-22
 PLP gene
Adult onset muscle weakness
Gynecomastia
Results in hemolytic anemia in
response to certain medications
such as antimalarials, fava
beans and some infections due
to a deficiency in G6PD enzyme
Drug induced hemolysis: NADPH is
one of the products of G6PD.
Glucose-6-phosphate
NADPH protects the cell against 400 million
dehydrogenase def.
oxidative damage by
affected
G6PD
regenerating reduced
glutathione  w/G6PD
deficiency, oxidant drugs causes
a dramatic severe acute
hemolytic anemia
Most common disease-producing
enzyme defect
OTC deficiency
Hunter’s Disease
Anhydrotic Ectodermal
dysplasia
Fragile X
FRAXX
Martin-Bell
Severe mental retardation
Most common monogenic form of
inherited mental retardation
Elongated face
Macroorchidism
Schizophrenia
Large testes and ears
MUT TRAITS
INHERITANCE
 Gain-of-fcn mut
 Majority are
duplications of PLP
region on X Chrm
X-Linked Recessive
 Most are missense
mutation (aa sub)
 Null mutation (miss
PLP, less severe)
 X Chromosome
 X q 11-12
 Androgen receptor
 46 XY
 Mut inactivates
androgen receptor
 Null mutation
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X-Linked Recessive
 Trinucleotide repeat
Can be dominant
 Gain-of-function
Allelic heterogeneity
X Chromosome
Xq12
Androgen receptor
CAG
X-Linked Recessive
Allelic heterogeneity
Provides some
resistance
to malaria
 X chromosome
 G6PD gene
 Dosage
compensation:
equalization of gene
activity despite
females having
twice the gene # of
X chromosome
 Pharamcogenetics
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X-Linked Recessive
X-Linked Recessive
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X-Linked Recessive
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 Incomplete
penetrance
 Non-mendelian
 Trinucleotide repeat
X-Linked Dominant
 Shermann Paradox
M F Dad normal
9% 5% kids
40% 16%
 Fragile X Chromo.
1/12-1500 M  Xq28 (long arm)
1/2000 F
 FMR-1 gene
 5’UTR CGG
CARRIERS
 X-inactivation
 Lyonization
 Expressed to the
same degree in
RBC of men and
women
X-Linked Recessive
Seen in
African,
Meditarran
ean and
Asian
descent
1/700
TESTING
GENETIC DISORDER FEATURES
INCIDENCE
ETIOLOGY
RECURRC
MUT TRAITS
INHERITANCE
Only females affected
Most common form of mental
retardation in females (severe)
Rett Syndrome (RTT)
Hand wringing
Spastic paraparesis w/ ataxia
Lethal to males fetuses
 X Chromosome
1:10-15,000
 Xq28
F
 MeCP2 gene
 Epigenetic
Imprinting
 Binds to methyl
bases
X-Linked Dominant
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Autosomal Recessive
Autosomal Recessive
Autosomal Recessive
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Autosomal Recessive
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Autosomal Recessive
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Autosomal Recessive
Autosomal Recessive
Autosomal Recessive
 hexoaminidase A
deficiency
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Autosomal Recessive
Adenosine Deaminase
Deficiency
Osteogenesis
Imperfecta
Galactosemia
Smith-Lemli-Opitz
(SLO)
Meckel-Gruber
Adrenal Insufficiences
Urea Cycle disorders
Methylmalonc aciduria
Biotidinase deficiency
Hurler Syndrome
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Autosomal Recessive
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Autosomal Recessive
Autosomal Dominant
Autosomal Recessive
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Autosomal Recessive
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Autosomal Recessive
Autosomal Recessive
Autosomal Recessive
Autosomal Recessive
Autosomal Recessive
Autosomal Recessive
Acute Intermittant
Porphyria (AIP)
Achondroplasia
Marfan’s Syndrome
Huntington’s Disease
Myotonic Dystrophy
Neurofibromatosis
Von Recklinhausen’s
Disease
Charcot-Marie-Tooth
CMT disease
ACHOO compelling
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Autosomal Dominant
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Autosomal Dominant
Autosomal Dominant
Autosomal Dominant
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Cystic Fibrosis
Sickle Cell Anemia
Thalassemia
Metachromatic
Leukodystrophy (MLD)
Ataxia Telangiectasia
(ATM)
Freidreich Ataxia
Phenylketonuria PKU
Spinal Muscular
Atrophy
Tay-Sachs
Storage disease
1/3000
CARRIERS
3% Ashkenazi
Jews
TESTING
GENETIC DISORDER FEATURES
helio ophthalmic
outburst
Familial
Hypercholesteremia
Polycystic kidney
disease
Reinoblastoma RBI
Wilm’s Tumor
Familial Polyposis Coli
Li Fraumeni
CML
Barlatt’s Lymphoma
Lip Pits
Malignant
Hyperthermia
Cleidocranial
pubodysplasia
MODY
KS
MERRF
MELAS
NARD
LHON
Neural Tube Defects
Pyloric Stenosis
Psychiatric disorders
Diabetes Mellitus
INCIDENCE
ETIOLOGY
RECURRC
MUT TRAITS
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INHERITANCE
Mitochondrial
Multifactorial
CARRIERS
TESTING