1. Chromosomal Abnormalities Jane Yoo HST.180 January 27, 2004

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

3. Human Karyotype

4. Idiogram of Human Karyotype

5. Cytogenetic disorders are characterized by an abnormal constitutional karyotype What mechanisms would result in cytogenetic abnormalities?

6. Nondisjunction in Meiosis I & Meiosis II

7. Chromosomal Rearrangments Translocation Translocation Deletion Deletion Duplication Duplication Inversion Inversion

8. Chromosomal Rearrangements

9. What is the diagnosis?

10. Trisomy 21 (Down Syndrome) The most common chromosomal disorder with an incidence of 1:700 live births in the US 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 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 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 Congenital heart disease; dysmorphic features; mental retardation; predisposition to leukemias; neurodegenerative changes; abnormal immune response and autoimmunity

11. Patient Interview 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 Chromosome 2

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

13. Genetic Imprinting 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

14. The Puzzle of Del(15)(q11q13) Mental Retardation Mental Retardation Ataxic gaitShort Stature Seizures Hypotonia Inappropriate laughter Obesity Hypogonadism

15. Genetic Imprinting

16. 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

17. FISH: Many Varieties Comparative Genomic Hybridization (CGH) Multicolor FISH Spectral Karyotyping

18. Interphase FISH 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

19. Cytogenetics and FISH 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

20. 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.

21. Ethical & Social Implications of PGD PGD has been used in several countries for sex selection Designer baby eugenics Creating babies to save siblings from a life-threatening disease