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Chromosomal Abnormalities
Jane Yoo
HST.180
January 27, 2004
Genetic Disorders
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Cytogenetic Disorders
Gross chromosomal abnormalities
Single Gene Disorders
Classical (Mendelian) inheritance
Non-classical inheritance
Mitochondrial genes
Trinucleotide repeats
Genetic imprinting
Human Karyotype
Idiogram of Human Karyotype
Cytogenetic disorders are characterized
by an abnormal constitutional
karyotype
What mechanisms would result in
cytogenetic abnormalities?
Nondisjunction in Meiosis I &
Meiosis II
Chromosomal Rearrangments
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Translocation
Deletion
Duplication
Inversion
Chromosomal Rearrangements
What is the diagnosis?
Trisomy 21 (Down Syndrome)
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The most common chromosomal disorder with an incidence of
1:700 live births in the US
95% trisomy 21; 4% Robertsonian translocation involving long
arm of 21; 1% mosaic
High correlation between maternal age and meiotic
nondisjunction leading to trisomy 21
Congenital heart disease; dysmorphic features; mental
retardation; predisposition to leukemias; neurodegenerative
changes; abnormal immune response and autoimmunity
Patient Interview
Chromosome 2
2p25.3 myelin transcription factor 1-like
2p21 protein kinase C, epsilon
2p12-p11.1 catenin (cadherin-associated
protein), alpha 2
2q14.3 caspr5 protein
2q21.2 low density lipoprotein-related protein
1B (deleted in tumors)
2q22.3 Rho GTPase activating protein 15
2q31.1-q31.2 myosin IIIB
2q33.3 amyotrophic lateral sclerosis 2
(juvenile) chromosome region, candidate 19
Single Gene Mendelian Disorders
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Structural Proteins
--Osteogenesis imperfecta and Ehlers-Danlos (collagens); Marfan syndrome
(fibrillin); Duchenne and Becker muscular dystrophies (dystrophin)
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Enzymes and Inhibitors
--Lysosomal storage disease; SCID (adenosine deaminase); PKU
(phenylalanine hydroxylase); Alpha-1 antitrypsin deficiency
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Receptors
--Familial hypercholesterolemia (LDL receptor)
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Cell Growth Regulation
--Neurofibromatosis type I (neurofibromin); Hereditary retinoblastoma
(Rb)
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Transporters
--Cystic Fibrosis (CFTR); Sickle Cell (Hb); Thalassemias (Hb)
Genetic Imprinting
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For most (non-imprinted) genes, the
maternal copy is functionally equivalent to
the paternal copy
Imprinted genes, however, are expressed
differently from maternal and paternal
alleles
In most cases, imprinting selectively
inactivates either the maternal or the
paternal allele of a particular gene
The Puzzle of Del(15)(q11q13)
Mental Retardation
Ataxic gait
Seizures
Inappropriate laughter
Mental Retardation
Short Stature
Hypotonia
Obesity
Hypogonadism
Genetic Imprinting
Fluoresence In Situ Hybridization
(FISH)
Fluorescent molecules paint
chromosomes to detect
abnormalities
Labeled probes hybridize to
complementary DNA
Three types of probes: locus
specific, centromeric repeat,
whole chromosome
FISH: Many Varieties
Spectral Karyotyping
Comparative Genomic
Hybridization (CGH)
Multicolor FISH
Interphase FISH
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Provides analysis of chromosomal aneuploidy from direct
amniocyte or chorionic villus sample (CVS) preparations
Screens for abnormalities in Chromosomes X, Y, 13, 18, 21
which account for 70% of chromosomal aneuploidy in the
second trimester
Subtelomeric probes allow for screening of terminal
rearrangements
Cytogenetics and FISH
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Interphase FISH was performed on direct CVS or amniocyte
preparations from 12 reciprocal translocation and 2 Robersonian
translocation pregnancies
Hybridization involved 1:1 mixture of Spectrum Green labeled pter
subtelomere and Spectrum Orange qter subtelomere probes
Fifty interphase nuclei were scored
Prenatal & Preimplantation Genetic
Diagnosis (PGD)
Involves creation of several in vitro embryos from
the eggs and sperm of a couple
Embryos develop to a 6-10 cell stage, at which
point one of the embryonic cells is removed and the
cellular DNA is analyzed for chromosomal
abnormalities
Embryos free of genetic abnormalities are
subsequently transferred to women’s uterus for
gestation. Embryos found carrying a genetic
abnormality are discarded.
Ethical & Social Implications of PGD
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PGD has been used in several
countries for sex selection
Designer baby eugenics
Creating babies to save siblings
from a life-threatening disease