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Genetics
Haplo-insufficiency: loss-of-function mutations in which half the normal levels of the gene product result in phenotypic
effects
- Cell membrane receptors (familial hypercholesterolemia)
- Acute intermittent Porphyria (enzyme deficiency, heme can’t be produced fast enough
- Osteogenesis Imperfecta Type 1
Dominant-negative mutations: mutant gene product interferes with the function of the normal gene product
- Example: collagenopathies OI type 2,3 or 4; Marfan Syndrome (defect in Fibrillin)
Gain-of-function mutations: result from increased levels of gene expression or the development of a new function of the
gene product
- Huntington disease and Achondroplasia
Loss of function mutations: result in either reduced activity (hypomorph) or complete loss of gene product (null allele or
amorph)  examples: enzyme deficiencies
Pleiotropy: disease causing mutation affects multiple organ systems
- Marfan Syndrome (AD) – mutation in fibrillin gene; skeletal abnormalities, hypermobile joints, ocular abnormalities,
cardiovascular disease
- Osteogenesis imperfecta – due to mutation in collagen gene
Allelic Heterogeneity: different mutations at the same locus cause the disease  may result in compound heterozygote
- Neurofibromatosis 1, Hemochromatosis, Cystic fibrosis (most common example of compound heterozygote)
Variable Expressivity: individuals who have inherited the same mutant allele, some individuals are severely affected and
others are mildly affected
- 3 reasons: random chance, other genetic factors (modifier loci), environmental response
- Hemochromatosis – more severe in males since females menstruate
- Xeroderma pigmentosum – more severe in individuals exposed frequently to environmental UV radiation
- Neurofibromatosis type 1 has high penetrance but variable expression (even in same family)
- Heteroplasmy in mitochondrial inheritance
Locus heterogeneity: mutations at different loci that cause the same disease phenotype
- Osteogenesis imperfect, Retinitis pigmentosa, Charcot Marie Tooth Disease (AD, AR, or X-linked)
New Mutation: mutation transmitted from an unaffected parent to an affected offspring (no family history of the
disease)
- Neurofibromatosis 1, Achondroplasia , Duchene Muscular Dystrophy, OI, Marfan Syndrome, X-linked disorders
- Increased Age of father is observed (in AD disease); mutation occurs during gamete formation (spontaneous) because
older fathers may contain more copy error mutations
Germline mosaicism: mutation in 2 infants of a father; mutation is present in proportion of the germline cells
Anticipation: individuals in the recent generations of a pedigree develop disease at an earlier age and with greater
severity (Triplet Repeat Expansion – Huntington’s)
Autosomal Dominant
- Presence of 1 mutant allele is sufficient
to cause disease – manifest in the
heterozygous state
- Skipped generations NOT common
(Vertical inheritance)
- Male to male transmission is seen
Myotonic Dystrophy (DM)
Mutation in the DMPK Gene – CTG
trinucleotide repeat expansion in the 3’UTR
- Most pleiotropic phenotype of all unstable
triplet repeat disorders
Characterized by:
- Wasting of the muscles
- Cataracts
- Arrhythmias
- Myotonia
- Maternal anticipation (variable age of
onset)
“My Tonia, My Testicles (testicular
atrophy), My Toupee (frontal balding), My
Ticker (arrhythmia) “
Achondroplasia
Mutation in the FGFR3 gene
- FGFR3 codes for a transmembrane receptor
that is involved in differentiation of
cartilage to bone
- Inhibits Chondrocyte Proliferation
- Dominant negative disorder; Gain of
function
Neurofibromatosis (NF1) Von Recklinghausen disease)
Mutation in neurofibromin (NF1) gene
[Chromosome 17]
- NF-1 is caused by different mutation in
the NF-1 Gene (allelic heterogeneity)
- Neurofibromin gene codes for a tumor
suppressor protein
Characterized by:
- Café-au-lait spots
- Neurofibromas: swellings on the skin
- Lisch nodules (pigmented iris harmatomas)
- Pheochromocytomas
- NF1 is a classic example of a disease that
exhibits variable expressivity
Neurofibromatosis Type 2
Gene affected – NF2 gene
Chromosome 22 – type 2 and NF2
Findings
- Bilateral acoustic schwannomas
- Juvenile cataracts
- Meningiomas + ependymomas
Familial Hypercholesterolemia (Type 2a)
High LDL with normal VLDL
Defective LDL-receptor
Characterized by:
- Xanthoma over tendon
- Xanthelasmas
- Childhood onset: risk of MI and death
- Adult onset: risk of coronary heart disease
Marfan Syndrome
Mutation in the fibrillin gene (chr 15)
- Expresses pleiotropy
- Dominant negative disorder
Characterized by:
- Skeletal abnormalities (long limbs,
pectus excavatum)
- Hypermobile joints
- Ocule abnormalities (myopia, lens
dislocation)
- Subluxation of lens (upward)
- Cardiovascular disease (mitral valve
prolapse, aortic aneurysm)
Osteogenesis Imperfecta
Mutation in collagen gene
Chromosome 17 (COL1A1
gene) or chromosome 7
(COL1A2 gene)
- Variable expressivity,
pleiotropy; locus
heterogeneity
Characterized by
- Multiple fractures
- Blue sclerae (translucent CT over
choroidal veins)
- Hearing loss (abnormal ossicles)
- Tooth abnormalities (lack of
denitn)
OI Type 1: classic OIpredisoposiiton to fractures, nondeforming, & blue sclera
OI Type 2: perinatal lethal OI due
to severe defects in collagen
formation
OI Type 3: progressively
deforming OI
OI Type 4: variable phenotype OI
but with normal sclera
Acute Intermittent Porphyria
Deficiency of hydroxymethylbilane synthase (porphobilinogen
deaminase)
- Porphobilinogen accumulates as the enzyme deficiency leads to a
block after porphobilinogen formation. Heme cannot be formed
and cannot feed-back inhibit ALA synthase
Characterized by:
- Very severe abdominal pain, abdominal colic
- Highly agitated state, tachycardia, respiratory problems, nausea
- Confusion, mental disturbance
- Weakness of lower extremities
- Patients are not photosensitive, but accumulation of ALA and
porphobilinogen at very high levels act as neurotransmitters
- Change of normal urine color to dark purple
color after exposure to light and air
- Colorless porphobilinogen is changed to the
dark colered porphobilin
Huntington Disease
Number of CAG repeats are found in the HD gene cluster that do
not present a disease phenotype and repeat numbers
- Increase in polyglutamine tract length causes Huntington
protein to aggregate, form inclusion bodies, and behave as a
toxin
- “Hunting 4 CAGs.” [Chr 4 and CAG repeat]
Neurodegenerative disease characterized by progressive dementia
and involuntary movements
- Degeneration of neurons in the cerebral cortex
- Chorea caused by degeneration of basal ganglia
- Cognitive and language decline (atrophy of caudate)
- Paternal anticipation
Hereditary Nonpolyposis Colon Caner
(HNPCC/ Lynch Syndrome)
Mutations in genes encoding mismatch repair
proteins: MSH2, MLH1, PMS1, PMS2, MSH6
- Results in micostatellite instability
- Frequently seen with tumors = simple repetitive
DNA sequences show size variability due to
inaccurate replication
Hereditary hemorrhagic Telangiectasia
Inherited disorder of blood vessels
Characterized by
- Branching skin lesions (telangiectasia)
- Recurrent epistaxis
- Skin discoloration
- Arteriovenous malformations (AVMs)
- GI bleeding
- Hematuria
Also known as
Osler-Weber-Rendu syndrome
Autosomal Recessive
Expressed in the homozygous state (aa)
- Usually seen in only one generation
(horizontal inheritance)
- Parents are usually carriers of the
disease; siblings are more commonly
affected
Hemochromatosis
Mutation of HFE gene
- Most common mutation is C282Y allele
(substitution of tyrosine for cysteine at
amino acid position 282)
- Other known mutations are HS63Daspartic acid is substituted for histidine in
position 63 and S65C
- Delayed age of onset
- Exhibits allelic heterogeneity and variable
expressivity
Sickle Cell Disease (HbSS)
Single point mutation in the β -globin gene –
Glutamic Acid is substituted by Valine at position
6 of the β-globin chain
- Hemoglobin S (HbS) moves slower to the
anode than HbA in hemoglobin
electrophoresis
- Heterozygotes (HbAS) possess sickle trait but it
is benign condition (develop clinical problems
in low oxygen saturation)
Characterized by:
- Individuals suffer sickle cell crisis episodes
- Caused by anemia, hemolysis, and
vasoocclusive ischemia around the
abdomen and long bones
GAG > GTG single nucleotide change
(point mutation; transversion)
SCIDS due to Adenosine Deaminase
Deficiency
Cystic Fibrosis
Mutation in the CFTR gene which encodes a protein (ABC type
Cl- Channel) expressed in the apical membrane of exocrine
epithelial cell
- Most common lethal inherited disease in Caucasians
- FΔ508 is the predominant mutation – deletes 3bp deletion
that eliminates a phenylalanine residue of CFTR at position
508 on the protein
- Allelic heterogeneity shows compound heterozygotes
Characterized by:
- Chronic bacterial infection of obstructed airways and
sinuses
- Fat malabsorption due to pancreatic exocrine insufficiency
- Infertility in males due to obstructive azoospermia (CAVD)
- Elevated sweat chloride levels
- Abnormally thick sticky mucus by several types of epithelial
cell
Alpha1-antitrypsin Deficiency (α1ATD,
AATD)
Mutations in SERPINA1
- Relatively common metabolic disorder in
Caucasian Population
- PI*Z is the most common deficiency allele
- 95% results from presence of 2 Z alleles –
Homozygosity leads loss of neutrophil
elastase inhibition that destroys lungs
- Smokers: methionine 358 of α1AT may be
oxidized reducing its affinity for elastase
(loss of function)
- Some PI*ZZ exhibit liver pathology –
polymers of AAT form due to mutation and
damages liver (in some children and some
adults)
- Liver pathology in this case is due to Gain
of Function of protein
Risk for lung disease in
heterozygotes:
- PI*MM – normal range,
normal alleles
- PI*MZ – slightly increased
risk for decreased lung
function
- PI*SZ – higher risk for lung Characterized by:
disease, especially in smokers - COPD in adults (specifically
emphysema) – smoking is the
(no risk for liver disease)
major factor
- PI*ZZ – highest risk for COPD
(even higher for smokers; and - Onset of respiratory disease in
smokers with AATD between 40-50
risk for liver disease)
years of age
- Non-smokers can be delayed to 60
years of age
Bloom Syndrome
Defect in BLM gene (15q26.1) = RecQL3 DNA
Helicase (required for replication repair,
recombination)
- Chromosomal instability resulting in many
chromosomal breaks and sister chromatid
exchanges
- Higher risk of a broad range of cancer types
Characterized by:
- Smaller than average
- Narrow chin, prominent nose and ears
- Facial rash (pigment and dilated blood
vessels) upon exposure to sun
- Often get diabetes and have neurological,
lung and immune system deficiencies
Fanconi anemia
Multiple genes involved – locus
heterogeneity (rare disorder)
- 8 different genes – Fanc A-H (all related
to DNA repair)
- Fanc A (16q24.3)
Increased spontaneous chromosome
breakage which is made worse by exposure
to DNA cross linking agents  significant
increased risk of neoplasia
Characterized by:
- Radial ray defects
- Pancytopenia
- Mental development problems
- Short stature
Xeroderma Pigmentosum (XP)
Mutation in 9 different NER genes  locus
heterogeneity
Nucleotide excision repair defect
Characterized by
- Extreme sun sensitivity = sunburn, blistering,
freckled with hyperpigmented skin lesions
- Ocular involvement = conjunctivitis, ocular
tumors
- Skin cancer including melanomas
- DNA damage is cumulative and irreversible
(formation of pyrimidine dimers)
Ataxia Telangiectasia
Defect in ATM gene
Serine threonine kinase with a number of
functions including: detecting DNA damage
(i.e. sensor) and activating cell cycle arrest and
DNA repair proteins (e.g. p53)
Characterized by:
- Affects cerebellum (= Ataxia) and immune
system
- Ocular telangiectasia (Angiomas)
- IgA deficiency
Findings
- Increase AFP
- Decrease IgA, IgG and IgE
- Lyphomopenia
Hemoglobin C
Hemoglobin C has a missense point
mutation at the 6th position of the β-globin
gene (Glu  Lys)
- HbC has lower solubility than HbA and
tends to crystallize in RBCs
- Can use Hemoglobin electrophoresis,
ASO and RFLP
Characterized by:
- Homozygotes HbC have mild hemolysis
α-Thalassemia
Caused by deficiency in α-globin chain synthesis 
α-globin gene deletion can be caused by
unequal crossing over during homologous
recombination
- Can result from deletion or inactivation of 2 αglobin genes (--/aa in cis configuration or a-/-a in
trans configuration)
Has 2 clinically significant forms:
- HB Bart Syndrome
- HbH disease
Hemoglobin Bart Hydrops fetalis (HB
Bart) Syndrome
- The most severe form of α-thalassemia
- Aggregation of γ4 tetramers (as there is a deficiency
of α-globin chains)
- All 4 α-globin alleles are deleted or dysfunctional
(inactivated)
Characterized by:
- Fetal onset of generalized edema, ascites, pleural
and pericardial effusions, and severe hypochromic
anemia
- Death in the neonatal period is almost inevitable
Hemoglobin H (HbH) disease
- HbH: aggregation of β4 tetramers (as there is
deficiency of α-globin chains); result of deletion or
dysfunction of three of the four α-globin alleles
- Microcytic hypochromic hemolytic anemia and
hepatosplenomegaly
- Mild thalassemia-like bone changes are present in
approximately 1/3 of affected individuals
- Is compatible with survival into adulthood
β-Thalassemia
Many mutations cause β-thalassemia (allelic
heterogeneity) – mutations in the HBB (β-globin) gene
on chromosome 11 (2 copies in an individual)
- β+ thalassemia: reduced gene expression
- Β0 thalassemia: complete suppression of gene
expression
- The net effect is the absent or reduced synthesis of
the β-globin chains of hemoglobin  excessive αglobin chains precipitate and result in severe
hemolytic anemia
- Bone marrow tries to compensate and expands
to perform erythropoiesis and this leads to
bone deformity
2 main forms:
- β-thalassemia major (‘Cooley’s Anemia’ and
Mediterranean Anemia’)
- Homozygotes or compound heterozygotes for β0 or
β+ genes – 2 severe mutations
- Mutations in both the β-globin genes
- Very low or absent HbA levels; high HbA2 and HbF
levels
- β-thalassemia minor
- Mostly heterozygotes; almost normal HbA levels
Summary of Hemoglobin
Intron inversion- Hemophilia A
Promoter mutation/splice site mutations- Beta-thalassemia
Gene deletions- alpha-thalassemia
Point mutations in exon-Sickle cell/HbC
Friedreich Ataxia
Progressive neuro-degenerative disease caused by a GAA trinucleotide repeat expansion in
intron 1 of the frataxin gene
- Repeat expansion alters chromatin structure involving DNA methylation of bases and histone
methylation >> transcriptional repression of the frataxin gene
- Presents in childhood as kyphoscoliosis
- Impairment in mitochondrial functioning
- Degeneration of multiple spinal cord tracts >> muscle weakness and loss of DTRs
Characterized by
- Ataxia and muscle weakness
- Vision and hearing impairment
- Scoliosis of the spine
- Diabetes
- Heart disorders – cause of death
- First symptoms are difficulty walking and loss of tendon reflexes in the ankle and knees
- Later slurring of speech and vision and hearing loss
Friedreich is Fratastic (frataxin): he’s your favorite frat
brother, always staggering and falling but has a
sweet, big heart.
Ataxic GAAit.
- GAA
- Staggering Gait
- Frequent Falling
- Diabetes
- Hypertrophic Cardiomyopathy
X-Linked Recessive Disorder
Males require only 1 copy of the mutation (hemizygous) to
express the disease – more common in males than females
Skipped generations common
- Mothers of affected sons are obligate carriers; daughters
of affected males are obligate carriers
- male to male transmission is not seen
Duchenne Muscular Dystrophy
Mutation of Dystrophin (DMD) gene
- Skewed X inactivation can result in
manifesting heterozygote
- Very large deletion – Frameshift or
Nonsense mutations
- Mutations that lead to Becker tend to
be less severe, typically an in-frame
effect
- Characteristics:
- Enlarged calves and wasting of
thigh muscles
- Dilated Cardiomyopathy
- Lethal before age of 30 (males
die) = very low reproductive
(genetic) fitness
Use multiplex PCR to detect
mutations in the dystrophin
gene
Normal dystrophin gene
used to anchor muscle
fibers
- Myonecrosis
- Increase CK and
aldolase
Hemophilia A
Inherited deficiency of clotting factor 8
Most of the severe mutations in coagulation
factor 8 (F8C) gene involve inversions of an
intron sequence
- Allelic heterogeneity
- Deficiency arises from a
large
inversion of an intron that disrupts
FVIII gene
- Characteristics:
- Bleed after minor trauma
- Develop a variable phenotype of
hemorrhage into joints and muscles,
easy bruising, and prolonged bleeding
from wounds
Hemophilia B (factor IX deficiency) are
clinically very similar and can only be
distinguished by assays of factor 8 and
factor 9 activity
- Point mutations and deletions in F9
gene
X-linked SCID
Due to defect in SCIDX1
Defect in the gamma-chain of the receptor for several
different interleukins (IL2RG)
- Also called the γc-cytokine receptor since
interleukins are cytokines
- If T-cells lack this receptor they cannot mature 
results in a deficiency of normal B-cell function
Triad
- Failure to thrive
- Chronic diarrhea
- Thrush
Findings
Absence of:
- Thymic shadow (CXR)
- Germinal centers (lymph node biopsy)
- T cells (flow cytometry)
Red/Green Color Blindness
Unequal intragenic recombination
between pair of X chromosomes
during meiosis
Non-lethal sex-linked diseases
Males are hemizygous for red/green
color blindness. 8% of the male
population is red/green color blind
Homozygous, color blind females (1 in
150) exist but are much rarer than
color blind males
X-linked Dominant Disorders
-
Skipping of Generations not common
Preponderance of females to males
No male to male transmission
Affected male transmits to all daughter but
none of the sons would be affected
Rett Syndrome
- Mutation in MECP2 gene (methyl-cytosine
binding protein 2)
- Binds to methylated cytosine bases
- Affects females more often males
- Males with the mutant X-gene, usually die
in utero or soon after birth
- EXCEPTION: boys with Kleinfelters
syndrome
Characterized by:
- Normal early development until 6
to 18 months followed by
developmental regression
- Loss of speech and acquired
hand skills
- Develop seizures, repetitive
hand movements, irregular
breathing and motor control
problems
- Compulsive hand wringing
- Gradual decrease in head growth
rate
Incontinentia pigmenti
Mutation of the X-linked IKBKG gene – inhibitor
of kappa light polypeptide gene enhancer in Bcells, kinase gamma
Characterized by
- Manifested as rashes and blisters in early life
- Later, patches of hyperpigmentation, marble
cake appearance of skin
- Mental retardation in some patients
- Retinal detachment in some patients
Patchy, darker
pigmentation where
mutant X is active;
normal pigmentation
where normal X is active
Y-linked Inheritance
- Only males are affected
- Genes on Y are primarily genes involved in
spermatogenesis and therefore mutations
usually cause sterility and are not passed
on
Mitochondrial Inheritance
- Inherited form the mother (only females
transmit the disease)
- All offspring of an affected female are affected
- Heteroplasmy: severity of disorder varies
depending on # of mitochondria with mutant
gene (variable expression)
Retinitis Pigmentosa
Digenic disorder – mutations in 2 genes (A,B)
are additive and necessary to produce the
disorder
This is a disease of progressive visual
impairment
- Painless, progressive vision loss beginning
with night blindness (rods affected first)
- Bone spicule–shaped deposits around
macula
Imprinting (parent of origin effects)
Characterized by mono-allelic expression
(ie. One of the parental alleles is silenced
and not expressed)
Some genes are active only when
transmitted by mother or father – maternal
loci or paternal loci are active
- This involves methylation of specific loci
(epigenetic change) & silencing of the gene
Prader Willi Syndrome (Papa)
Deletion of Paternal 15q11-13 (absence of
SNRPN)
- Microdeletion of this region in paternal
chromosome
- Detected by FISH using specific probes
against the region
Characterized by:
- Usually obese, mental and developmental
delay, underdeveloped genitalia
- Hypotonia in infancy, failure to thrive
Prader Willi Syndrome – Uniparental
Disomy (phenomenon of trisomy rescue)
Methylation sensitive restriction
enzyme analysis – exploited by
Southern and MLPA methods
Angelman Syndrome – “Happy Puppet
Syndrome”
Deletion of maternal 15q11-13 (absence of active
UBE3A gene)
- Increased in in vitro fertilization children
Characterized by
- Happy disposition, laugh inappropriately
- Severe mental retardation, seizures
- Puppet like posture of limbs
Fragile X Syndrome (Martin-Bell
Syndrome)
Triplet repeat expansion (CGG repeat) on the X
chromosome
Triplet repeat is present at 5’ UTR of the FMR1 gene –
resulting in increased methylation of this region and
silencing of the FMR1
Southern Blot analysis: gives
indication of # of triplet repeat
sequences
Cytogenetic test: X Chromosome
show breakage (fragile X) in a folate
deficient medium
Characterized by:
- Intellectual disability
- Prominent ears
- Long face and large eyes that stick out, long jaw
- Flat feet, low muscle tone
- Macro orchidism (enlarged testis)
- Autism
- Mitral valve prolapse
Chromosome Abnormalities
Numerical
Structural
Euploidy (polyploidy) - # of chromosomes in
multiples of 23
- Translocations
◦ Triploidy: contain 3 copies of each chromosome
(69); not compatible with life
◦ Tetraploidy: contain 4 copies of each chromosome
(92). Lethal
Aneuploidy
- Monosomy: loss of a chromosome, not compatible
with life (Except Monosomy X/ Turner Syndrome)
- Trisomy: Presence of an additional chromosome
- Autosomal Trisomy
- Trisomy 21 (Down Syndrome)
- Trisomy 18 (Edward Syndrome)
- Trisomy 13 (Patau Syndrome)
- Sex Chromosome Aneuploidy
- Klinefelter Syndrome (47, XXY)
- Turner Syndrome (45,X)
◦ Reciprocal
◦ Robertsonian
- Deletions
- Inversions
- Ring Chromosome
- Isochromosome
Reciprocal Translocation
Alternate segregation: Balanced chromosomal
material
-In a reciprocal translocation carrier, alternate
segregation can result in
1. Normal games
2.Gamete that has a reciprocal translocation
like the parent (balanced). When fertilized,
results in translocation carrier.
Adjacent segregation: unbalanced gametes
(gametes with partial trisomy and partial
monosomy of chromosomes). On fertilization
result in unviable fetuses and spontaneous
abortions.
Trisomy 21 (Down Syndrome)
- Most common Autosomal
- Risk factor: increased maternal age, increases risk of
meiotic nondisjunction during oogenesis (most common is
meiosis 1 nondisjunction)
- Features:
- Intellectual disability
- Short stature
- Depressed nasal bridge, upslanting palpebral fissures,
epicanthal folds
- Congenital heart defects
- Single palmar crease
- Develop changes similar to Alzheimer disease at a
relatively young age. One of the genetic factors
responsible for Alzheimer is localized to chromosome
21
Trisomy 18 (Edward Syndrome)
Genetic mechanism is nondisjunction during
oogenesis
Features:
- Clenched fist, overlapping of fingers
- Rocker bottom feet
- Congenital heart defects
- Low-set ears, small lower jaw
(micrognathia)
- Microcephaly
- Intellectual disability
Trisomy 13 (Patau Syndrome)
Genetic mechanism is nondisjunction during
oogenesis
Features;
- Polydactyly
- Cleft lip and palate
- Micropthalmia
- Microcephaly
- Intellectual disability
- Cardiac anomalies
Disorders of Sexual Development
Turner Syndrome (45,X)
Genetic mechanism responsible for Turner
Syndrome is nondisjunction during meiosis
- X chromosome monosomy
- Short stature
- Webbed neck, cystic hygroma at birth
(neck swelling)
- Primary amenorrhea
- Gonadal dysgenesis
- ‘streak ovaries’
- Broad chest
Klinefelter Syndrome (47,XXY)
Genetic mechanism responsible for
Klinefelter Syndrome is nondisjunction
during meiosis
- Testicular atrophy
- Gynecomastia
- Female distribution of hair
- Infertility
Presence of a Barr body in the buccal
mucosal cells
May be caused by nondisjunction
during meiosis 1 or 2 in the mom,
or nondisjunction during meiosis 1
in dad (meiosis 2 nondisjunction in
dad cannot result in Klinefelter
Syndrome)
Cri du chat Syndrome
Chromosome loses some of its genetic material
Deletion of chromosome 5p
46,XX, del(5) (p15.3) (pter) or
46,XY,del(5)(p15.3)(pter)
-mainly use fish or CGH for diagnosis.
-if deletion is known use FISH
-if deletion is unknown is Array CGH
Characterized by:
- High pitched, cat like cry
- Severe intellectual disability
- Speech problems
- Microcephaly
- Cardiac anomalies (VSD)
DiGeorge Syndrome (Velocardiofacial
Syndrome; 22q11 deletion syndrome)
Microdeletion of chromosome 22q
-Use array CGH to diagnose
Characterized by
- Congenital heart defects
- Absence of thymus (thymic aplasia) –
immunological problems due to
underdevelopment
- Cleft lip & palate
- Learning disability
- Facial anomalies include narrow palpebral
fissures and prominent nasal root
- Increased risk of schizophrenia
WAGR Syndrome
Small micro deletions
Wilms’ tumor
Aniridia
Genitouriniary malformations
Retardation of growth and development
Metaphase spread showing
chromosome 11 (double arrow).
Chromosome indicated by
single arrow has an interstitial
deletion in short arm
FISH showing failure of a PAX6
locus specific probe (red) to
hybridize to the deleted
chromosome 11 shown in A
from a child with WAGR
syndrome.
Genetic Tests Overview
Arrays are composed of hundreds to millions of probes which are complimentary to a region in
the genome
Detect copy number changes
PCR vs. Southern Blot– PCR is faster and more convenient. Some applications still require PCR
like: methylation sensitive restriction digest followed by southern blot to detect methylated
cytosines in CpG island and detection of genomic regions which are resistant to PCR
amplfications such as regions which have too high a percentage of GC pairs
Molecular
ARRAY CGH
SNP CHIP ARRAY
-detects copy number variants
-polymorphic probes (single nucleotide
variants)
can only detect unbalanced chromosomal
abnormalitites—balanced reciprocal translocations,
robertsonian translocation
-does not require probe with deletion
–Limitations:
-inability to detect structural chromosomal abberations
without copy number changes
(mocaisism, reciprocal translocations, inversions, or
ring chromosomes do not affect copy number)
-cannot detect centromeres, telomeres (these regions
are highly repetitive)
-provides copy number and LOH in one assay
-used for uniparental disomy
-used to detect tumors (wilms tumor-LOH)