genetic disorders m. kent froberg, m.d. 2009. objectives learn the basic characteristics of...
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GENETIC DISORDERS
M. Kent Froberg, M.D.
2009
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Objectives
• Learn the basic characteristics of cytogenetic, Mendelian and non-classical inherited disorders
• Be able to distinguish features of autosomal dominant, autosomal recessive and X-linked genetic disorders
• Understand the pathogenesis of the most common genetic diseases
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GENETIC DISORDERS:METHOD OF STUDY
• Classical genetics: requires knowledge of gene
product to ID gene
• Reverse genetics: protein unknown, use marker
linkeage to locate gene of interest
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DISORDERS
• Chromosomal: # or structure, ex. trisomy 21
– Good for cytogenetic ID
• Mendelian disorders: Mutant genes of large effect (SCD), often requires molecular techniques
• Multifactorial: polygenetic + environment (DM, HTN, CHD)
– Less amenable to genetic studies
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CYTOGENETICS (1)
• Cytogentic disorders identified through karyotyping
• Karyotyping: visual image of chromosomes– NL karyotype 46 xx (xy) – 22 homologous pairs + sex chr.
• Method: – Cell culture (usually peripheral blood
lymphocytes)– Arrest in metaphase (colchicine)– Stain G banding (Giemsa stain)
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CYTOGENETICS (2)
• Method (cont.):
– Light and dark bands, sort by size
– Banding pattern
– Centromere location:
• metacentric: middle
• submetacentric: off-center
• acrocentric: near end
• telocentric: not in humans
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CYTOGENETICS (3)
• Limitations:
– Requires viable cells, visible changes (4 mil bp)
• Advantages:
– Good for aneuploidy, large structural changes, del, t, i
– Examples:
• 47, xy, +21
• 46, xx, del 5q-
• 46, xy, t(9;22)
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MUTATIONS (1)
• Definition: heritable alteration in genome
• Types:
– Substitution: point mutation
– Insertion: alters reading frame
– Deletion: alters reading frame, i.e., frameshift
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MUTATIONS (2)
• Consequences:
– Codon mutations:
• Missense: one AA for another
–Ex.: CTC to CAC, glu to val in SCD
• Nonsense: stop; CAG to UAG = stop
–Ex: thal
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MUTATIONS (3)
• Consequences (cont.):
– Noncoding sequence:
• Promoter or enhancer: decreased or no transcription
• Introns: defective splicing, most common cause -thal
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CYTOGENETIC DISORDERS
• 50% of early abortions, 5% stillbirths, .5-1% livebirths
• Aneuploid = < 46 >
– Secondary meiotic nondisjunction or anaphase lag
– Monosomy (autosomal usually fatal) and trisomy (some viable)
• Mosaicism = 2 or more cell lines in genome
– Secondary early mitotic errors
– Most common with sex chr. and Down syndrome
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CYTOGENETIC DISORDERS
• Chromosome breakage syndromes– Autosomal recessive– Have increased risk of CA– Multi-organ system changes:
• Fanconi anemia: developmental problems, aplastic anemia, myelodysplasia, leukemia
• Bloom syndrome: short stature, photosensitivity, risk cancer
• Ataxia-telangectasia:
neurodegenerative disorder, risk ALL & lymphoma
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CYTOGENETIC DISORDERS
• Rearrangements:
– Reciprocal translocation: usually compatible with life, but associated with CA or abnl offspring
– Robertsonian translocations: centric fusion of acrocentric chr. (rRNA from p of 13, 14, 15, 21, 22), abnl offspring
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CYTOGENETIC DISORDERS
• Rearrangements (cont.):
– Isochromosome: one arm lost, other duplicated & fused to centromere, so two p or two q (iXq)
– Ring: deletion at both ends & fusion (2 breaks)
– Inversions: compatible with NL development
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Origins and examples of
triploidy, trisomy and
monosomy
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Most common
trisomies
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CYTOGENETIC DISORDERS
• Trisomy 21 (Down Syndrome): most common chr disorder, causes MR
– Incidence ~1/800; 95% extra chr., 4% Robertsonian trans (familial), 1% mosaics (milder MR)
– Correlated with maternal age: incidence <20 ~1/1550, >45 ~1/25. Due to maternal meiotic non-disjct in 95%
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CYTOGENETIC DISORDERS
• Trisomy 21 (Down Syndrome) (cont.):
– CSx:
• flat face, oblique palpebral fissures, epicanthal folds, severe MR ( IQ 25-50 in 80% ),
• congenital heart disease (40%), ALL & AML ~10-20x risk, Alzheimer Disease at ~40,
• abnl immune response (lung infections & thyroid disorders)
• 80% survive >30 years
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Mosaic with subtle features of trisomy 21
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CYTOGENETIC DISORDERS
• Other trisomies (cont.):
– 18 (Edward Syndrome):
• 1/8000 births, overlapping fingers, MR, low set ears, heart defects
– 13 (Patau syndrome):
• 1/6000, heart defects, polydactyly, cleft lip & palate, microphthalmia, MR
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Features of trisomy 13
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Facies of trisomy 13
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Trisomy 18
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CYTOGENETIC DISORDERS
• Cri du chat (5p- syndrome):
– Severe MR
– Microcephaly
– Round face
– Some survive to adults
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CYTOGENETIC DISORDERS
• Sex chromosome disorders:
– More common than autosomal, better tolerated because of lyonization & lack of genetic material of Y chr: lyonization (16th day embryonic life, Xist gene, secondary methylation).
• subtle/chronic problems sexual development & fertility
• often 1st recognized at puberty
• more Xs ~ more likely MR
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CYTOGENETIC DISORDERS
• Klinefelter Syndrome: Male hypogonadism; 1 or more Ys & 2 or more Xs
– 82% = 47, XXY, ~50% from 1st meiotic paternal non-disjct, 15% mosaics, incidence 1/850 live male births
– Principal cause male infertility
– Testes: tubular atrophy, prominent Leydig cells
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CYTOGENETIC DISORDERS
• Turner Syndrome: monosomy X, hypogonadism in phenotypic female
– 45, X (57%) but only 1% survive to birth
• del Xp, i (Xq), or partial del of Xp or Xq
• so variable phenotypes
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CYTOGENETIC DISORDERS
• Turner syndrome (cont.):
– CSx: edema in infancy in most severely affected =
cystic hygroma,
– congenital HD esp. coarctation of aorta
– Later: #1 cause primary amenorrhea, short stature, webbed neck, broad chest, widely spaced nipples
– Streak ovaries secondary to accelerated loss of oocytes by 2 years
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Cystic hygroma in female stillborn fetus
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Edema of the hand in newborn with Turner Syndrome
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Short stature and webbed neck of Turner Syndrome
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CLASSICAL GENETIC DISORDERS (MENDELIAN)
• Expressed mutations in single genes of large effect (sickle cell anemia)
– Pleiotropism: multiple end effects
– Genetic heterogeneity: same effect by mutations at several genetic loci
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TRANSMISSION PATTERNS
• Autosomal dominant:
– Manifested in heterozygous state
– Affects males & females
– Affected X unaffected = 50% transmission
– Some due to new mutations
– Clinical features modified by variable expressivity (seen in all with gene, but expressed differently) & reduced penetrance (i.e., 50% of those with gene express trait)
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TRANSMISSION PATTERNS
• Autosomal dominant (cont.):– Age of onset may be delayed• Huntington Disease
– Often structural protein or transport protein• hereditary spherocytosis• Marfan syndrome• familial hypercholesterolemia• NF• tuberous sclerosis
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TRANSMISSION PATTERNS
• Autosomal recessive:
– Single largest category Mendelian disorders
– Parents not affected
– Siblings 1 in 4
– Expression more uniform
– Penetrance usually complete
– Onset early in life, new mutations undetected
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TRANSMISSION PATTERNS
• Autosomal recessive (cont.):
– Enzymes involved
– Heterozygote has 1/2 nl & 1/2 abnl
• inborn errors of metabolism
• CF, SCD, PKU, 1-antitrypsin deficiency, most storage diseases, Ehlers-Danlos
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TRANSMISSION PATTERNS
• X-linked:
– All sex-linked are X-linked
– Most recessive
– Male is hemizygous for X so expressed in males
– Sons of affected male not affected
– Daughters carriers
– Sons of heterozygous female have 1 in 2 chance
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TRANSMISSION PATTERNS
• X-linked (Cont.):
– Female may be affected because of skewed lyonization
– Usually partial expression (G6PD def.)
– Examples:
• DMD
• hemophilia
• Wiscott-Aldrich
• chronic granulomatous disease
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BIOCHEMICAL BASIS OF MENDELIAN DISORDERS
• Direct effect on protein or indirect–consequences:– accumulation of substrate or abnl product
• Enzyme defects: – Decrease end-product: albinos - no melanin
secondary to deficiency of tyrosinase– Increased substrate: phenylalinine-PKU– Failure to inactivate toxic substrate
-antitrypsin deficiency
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BIOCHEMICAL BASIS OF MENDELIAN DISORDERS
• Receptor or transport defect:
– Failure to cross cell membrane (familial hypercholesterolemia)
• Structural protein defect:
– Affects function (DMD, SCD)
• Adverse drug reactions:
– Oxidative injury (G6PD def)
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SPECIFIC DISORDERS
• Marfan Syndrome: connective tissue disorder, 70-85% autosomal dominant, variable expression– Marfanoid appearance: tall, long fingers, lax
joints, dolicocephalic, frontal bossing, scoliosis, kyphosis, ectopia lentis, aortic cystic medial degeneration (dissection cause of death in 30-40%)
– Cause: defective fibrillin (extracellular matrix protein for elastin, mapped to 15q21.1)
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Section of aorta with cystic medial
degeneration
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Cystic medial degeneration
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Smooth muscle cells of media (arrows) are separated by cystic spaces
and basophilic material
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Lack of elastin staining
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SPECIFIC DISORDERS
• Ehlers-Danlos Syndrome:
– Heterogeneous group of defects of collagen synthesis or assembly
– Inheritance by all three Mendelian patterns
– Variable phenotypes
– Largely affects skin & ligaments
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RECEPTOR DEFECTS
• Familial hypercholesterolemia: due to mutation in gene for LDL receptor–loss of feedback control– Increased cholesterol– Early AS & MI – Mendelian disorder: multiple mutations– Heterozygous (1 in 500): increased cholesterol 2-3X, increased
AS & xanthomas– Homozygous: 5-6X increased cholesterol, early AS, MI in 20s
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ENZYME DEFECTS
• Lysosomal Storage Diseases:
– Membrane-bound bags of hydrolytic enzymes, autophagy & heterophagy
– Enzyme defect leads to substrate accumulation in cell
– Mutations may affect enzyme activator, post-translational processing, substrate activator, lack of transport protein
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GANGLIOSIDOSIS
• Tay Sachs (GM2) most common of 3 types affecting
hexosaminidase A, all with similar phenotypic effects
– Eastern European Jews (carrier rate 1 in 3)
– Gangliosides accumulate in all tissues but neurons in CNS & retina affected most (ballooning degeneration with oil red o-positive vacuoles)
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GANGLIOSIDOSIS (Cont.)
• Tay Sachs (GM2) (Cont.):
– NL at birth–CSx by 6 months–mental and motor deterioration, blindness, cherry-red spot on macula
– Multiple mutations on Chr 15 (Sandoff & activator def on chr 5)
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A. Nerve cell body distended with
gangliosides
B. EM of lysosomes with whorled
configurations in neuron of Tay-
Sachs Disease patient
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NIEMANN-PICK DISEASE
• Heterogeneous group that lead to accumulation of sphingomyelin & cholesterol
• Two major types
• Type A accounts for 75-80% (def. sphingomyelinase)
– Severe infantile form, CSx by 6 months
– Viscera & CNS affected (hepatosplenomegaly)
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NIEMANN-PICK DISEASE (Cont.)
• Type A (Cont.):
– Skin xanthomas
– Small uniform lipid vacuoles accumulate in mononuclear phagocytes and neurons with increase in size to 90
– Spleen to 10X NL
– Retinal cherry-red spot in 1/3 to 1/2
– Have FTT, generalized lymphadenopathy, progressive psychomotor deterioration, death 1-2 yrs
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Spleen of patient with Niemann-Pick Disease. The red pulp is expanded with
lipid-laden histiocytes. Arrows indicate white pulp.
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Phagocytes in splenic red pulp contain many small vacuoles filled with
sphingomyelin.
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GAUCHER DISEASE
• Group of autosomal recessive disorders with defect in glucocerebrosidase
– Most common lysosomal storage disorder
– Cleaves glucose from ceramide
– Accumulates in macrophages
– Three clinical subtypes
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GAUCHER DISEASE (Cont.)
• Type 1:
– 99%
– Chronic non-neuropathic form
– Accumulation esp. in spleen & bone marrow, esp. European Jews
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GAUCHER DISEASE (Cont.)
• Gaucher cells in spleen, liver, bone marrow: fibrillary distended cytoplasm (PAS-positive)
• CSx: 1st appear in adult life, often pancytopenia
or thrombocytopenia secondary to hypersplenism
– May have bone pain or pathologic fractures, but compatible with long life
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Gaucher cells in bone marrow have pale, granular cytoplasm
with a fibrillar appearance
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Lymph node filled with pale, eosinophilic histiocytes in Gaucher
Disease
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Gaucher cells fill alveoli in lungs of patient with long-
standing disease
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PAS positive (left) and unstained histiocytes (right) in Gaucher Disease
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MUCOPOLYSACCHARIDOSES (MPS)
• Group of deficiencies of degradation of glycosoaminoglycans, accumulate within macrophages and endothelium
– MPS I H: Hurler syndrome, def -L-iduronidase, most severe form of MPS
• NL at birth
• 6 mos hepatosplenomegaly
• skeletal deformities
• death in 6-10 yrs of CV complications
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MUCOPOLYSACCHARIDOSES (MPS) (Cont.)
– MPS II H: Hunter syndrome
• X-linked
• milder CSx
• no corneal clouding
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GLYCOGEN STORAGE DISEASES
• Glycogenoses: deficiency of one of enzymes of glycogen synthesis or degradation, liver and muscle target organs, Types I-VIII
– Hepatic forms: von Gierke disease (Type I), def. G-6-phosphatase
• hepato-renomegaly: glycogen in cortical tubular epithelium, hypoglycemia, FTT, bleeding tendency, 50% mortality
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GLYCOGEN STORAGE DISEASES (Cont.)
– Myopathic forms: McArdle syndrome (Type V), def. muscle phosphorylase
• accumulation of subsarcolemmal glycogen
• painful cramps after exercise without increase in venous lactate
• normal longevity
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CELL GROWTH GENE DEFECTS
• Most in somatic cells–CA, ~5% transmitted through germline, proto-oncogenes and tumor-suppressor genes
– Neurofibromatosis-1 (von Recklinghausen disease): 1/3000, 50% autosomal dominant, penetrance 100% but variable expressivity. Have:
• multiple neural tumors
• numerous pigmented skin lesions (90%)–”cafe au lait” spots
• iris hamartomas–Lisch nodules
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CELL GROWTH GENE DEFECTS (Cont.)
– Neurofibromas:
• Arise from nerve trunks in skin
• Soft, multinodular tumors 1 cm to > 20 cm (plexiform)
• Contain all elements, i.e., proliferating neurites, Schwann cells and fibroblasts within loose myxoid stroma
• Mal transformation 3%
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CELL GROWTH GENE DEFECTS (Cont.)
– NF-1: Gene mapped to chr 17q11.2, variable expression, pts also have bone cysts, scoliosis, meningiomas, optic gliomas
– NF-2: Bilateral acoustic schwannomas, may not have skin tumors, no Lisch nodules, mapped to chr 22
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MULTIFACTORIAL INHERITANCE
• Increased risk if parents severely affected
• Greatly modified by environment
• Risk in sibling of affected child same (2-7%)
• Ex: DM, cleft lip and palate, CHD, HTN
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NONCLASSIC INHERITANCE
• Triple repeats
• Genomic imprinting
• Mutations in mitochondrial genes
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NONCLASSIC INHERITANCE:TRIPLE REPEAT MUTATIONS
• Fragile X, HD, myotonic dystrophy
– Fragile X: One of most common forms of familial MR, X-linked, IQ 40-70, macro-orchidism in 80%, long face, large mandible, large everted ears
• 20% of affected males are carriers, 30% of carrier females have MR, anticipation = clinical features worsen with successive generations
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NONCLASSIC INHERITANCETRIPLE REPEAT MUTATIONS
– Fragile X (Cont.):
• Mechanism: nl to have 6-54 tandem repeats of CGG at Xq27
• “Premutations”: 52 - 200 CGG repeats
• “Full mutations”: 250 - 4000 repeats, amplified in oogenesis
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Trinucleotide repeat blot showing pre- and full mutations.
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NONCLASSIC INHERITANCE:GENOMIC IMPRINTING
• “Parent of origin” effects, one parent expressed for given gene– Prader-Willi & Angelman syndromes: same
area deleted; del15q11-13– PWS: MR, short stature, hypogonadism, FTT
early, obesity later, all cases del is in paternal chr 15
– AS: MR, ataxic gait, SZ, inappropriate laughter = “happy puppets,” have deletion on maternal chr 15
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NONCLASSIC INHERITANCE:GENOMIC IMPRINTING (Cont.)
– Mechanism: methylation of DNA
– Some cytogenetically nl have two copies of 15 from one parent = uniparental disomy
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Genomic Imprinting as seen in Pader-Willi and Angelman Syndromes
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mat.
pat.
Deletion
pat.
mat.
mat.
mat.
Prader-Willi syndrome Angelman syndrome
pat.
pat.
Uni-parentaldisomy
mat.
pat.
PWS AS PWS AS
Normal
PWS AS
= active gene = inactive gene
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Angelman Syndrome
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MOLECULAR DIAGNOSIS
• Detection of inherited mutations
• Detection of acquired mutations in neoplasia
• Dx & classification of hematopoietic neoplasms
• Dx of infectious diseases (TB & HIV)
• Determination of relatedness & identity in transplantation, paternity testing and forensic medicine
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MOLECULAR DIAGNOSIS (Cont.)
• Advantages:
– Very sensitive (can be disadvantage)
– Cells need not be alive
• any cell works (except mature RBCs)