Chromosomal Abnormalities Jane Yoo HST 180 January 27

Chromosomal Abnormalities Jane Yoo HST. 180 January 27, 2004

Genetic Disorders Cytogenetic Disorders Gross chromosomal abnormalities n Single Gene Disorders Classical (Mendelian) inheritance Non-classical inheritance Mitochondrial genes Trinucleotide repeats Genetic imprinting n

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 Translocation n Deletion n Duplication n Inversion n

Chromosomal Rearrangements

What is the diagnosis?

Trisomy 21 (Down Syndrome) n The most common chromosomal disorder with an incidence of 1: 700 live births in the US n 95% trisomy 21; 4% Robertsonian translocation involving long arm of 21; 1% mosaic n High correlation between maternal age and meiotic nondisjunction leading to trisomy 21 n Congenital heart disease; dysmorphic features; mental retardation; predisposition to leukemias; neurodegenerative changes; abnormal immune response and autoimmunity

Patient Interview Chromosome 2 2 p 25. 3 myelin transcription factor 1 -like 2 p 21 protein kinase C, epsilon 2 p 12 -p 11. 1 catenin (cadherin-associated protein), alpha 2 2 q 14. 3 caspr 5 protein 2 q 21. 2 low density lipoprotein-related protein 1 B (deleted in tumors) 2 q 22. 3 Rho GTPase activating protein 15 2 q 31. 1 -q 31. 2 myosin IIIB 2 q 33. 3 amyotrophic lateral sclerosis 2 (juvenile) chromosome region, candidate 19

Single Gene Mendelian Disorders n Structural Proteins --Osteogenesis imperfecta and Ehlers-Danlos (collagens); Marfan syndrome (fibrillin); Duchenne and Becker muscular dystrophies (dystrophin) n Enzymes and Inhibitors --Lysosomal storage disease; SCID (adenosine deaminase); PKU (phenylalanine hydroxylase); Alpha-1 antitrypsin deficiency n Receptors --Familial hypercholesterolemia (LDL receptor) n Cell Growth Regulation --Neurofibromatosis type I (neurofibromin); Hereditary retinoblastoma (Rb) n Transporters --Cystic Fibrosis (CFTR); Sickle Cell (Hb); Thalassemias (Hb)

Genetic Imprinting n n n 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)(q 11 q 13) 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 Multicolor FISH Spectral Karyotyping Comparative Genomic Hybridization (CGH)

Interphase FISH n Provides analysis of chromosomal aneuploidy from direct amniocyte or chorionic villus sample (CVS) preparations n Screens for abnormalities in Chromosomes X, Y, 13, 18, 21 which account for 70% of chromosomal aneuploidy in the second trimester n Subtelomeric probes allow for screening of terminal rearrangements

Cytogenetics and FISH n n n 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 n n n PGD has been used in several countries for sex selection Designer baby eugenics Creating babies to save siblings from a life-threatening disease