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MENDELIAN INHERITANCE 2002 • • • • • • • Genotype Phenotype Locus Allele Homozygote/ Heterozygote Compound heterozygote Proband A. B. C. D. E. AD AR XLR XLD Not genetic Mozart’s Piano Concerto in Amajor is Köchel number • • • • • A B C D E K365 K450 K482 K488 K491 Clinical vignette • S G: 20 yo college student – Spontaneous rupture of the common iliac artery – Friable tissues, extensive bleeding – Past history: • Easy bruising • Lax joints (fingers, elbows, left shoulder) • D G: 53 yo mother of SG – Spontaneous perforation of the sigmoid colon – Past history • Easy bruising • No joint laxity • Two normal pregnancies Laboratory analysis • Skin fibroblasts: abnormal type III collagen • COL3A1 DNA analysis: Gly25Val • Diagnosis: Ehlers-Danlos Syndrome, Type IV Pedigree symbols Autosomal dominant inheritance • • • • Vertical Males and females affected Males and females transmit Each affected has one affected parent… NF1 Neurofibroma Café-au-lait Lisch Nodules Neurofibromatosis 1 variable expressivity • • • • • • • Café-au-lait spots Axillary freckling Lisch nodules Cutaneous neurofibromas Plexiform neurofibromas Scoliosis CNS tumors Marfan syndrome Marfan ectopia lentis Marfan life expectancy Marfan Syndrome variable expressivity Incomplete penetrance AD Erythermalgia Achondroplasia What is the risk that this couple’s child will have achondroplasia ? • • • • • A B C D E ¼ ½ ¾ 1 0 Achondroplasia mutations in FGFR3 Allelic Heterogeneity COL3A1 (EDS IV) Autosomal Recessive Autosomal Recessive • Horizontal • Males and females affected • Parents of affected are normal Autosomal recessive A. B. C. D. E. AD AR XLR XLD Not genetic Locus Heterogeneity congenital deafness IV-1,2,3,4,5,6 are all double heterozygotes X-linked recessive X-linked recessive inheritance • • • • • “Diagonal” Males affected… Transmitted by carrier females NO male-to-male transmission Daughters of affected males are obligate carriers X-linked recessive inheritance X-linked dominant X-linked NOT sex-linked Mitochondrial inheritance • Mitochondrial DNA – – – – 2 to 100 mitochondria/cell 5 to 10 chromosomes/mitochondrium 16.5 kb mt DNA 37 genes • Mitochondrial inheritance – Maternal – Heteroplasmy MERRF MERRF Pedigree Heteroplasmy Myotonic Muscular Dystrophy • Most common inherited muscular dystrophy of adults • Muscle wasting—face, neck, distal muscles • Myotonia • Cardiac and smooth muscle affected • Cataracts • Immunoglobulin abnormalities • Insulin resistance • Occ. Mild MR Autosomal dominant ANTICIPATION DENIAL AIN’T JUST A RIVER IN EGYPT -Rap song The absence of evidence is NOT equivalent to evidence of absence Triplet (CTG) Repeats Repeat Expansion Triplet Repeat Diseases Pathogenesis of Myotonic Dystrophy • Loss of Function – Haploinsufficiency of DMPK – Cis-chromatin effects Cis-chromatin effects Pathogenesis of Myotonic Dystrophy • Loss of Function – Haploinsufficiency of DMPK – Cis-chromatin effects • Gain of Function Gain of Function Ypsilanti Demetrius Ypsilanti Alexander Ypsilanti
