MENDELIAN INHERITANCE 2002 Genotype Phenotype Locus Allele Homozygote

MENDELIAN INHERITANCE 2002 • • Genotype Phenotype Locus Allele Homozygote/ Heterozygote Compound heterozygote Proband

A. B. C. D. E. AD AR XLD Not genetic

Mozart’s Piano Concerto in Amajor is Köchel number • • • A B C D E K 365 K 450 K 482 K 488 K 491

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 • COL 3 A 1 DNA analysis: Gly 25 Val • 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…

NF 1 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 FGFR 3

Allelic Heterogeneity COL 3 A 1 (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 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