GENETIC AND PHYSICAL MAPPING OF THE MCKUSICK-KAUFMAN-SYNDROME

McKusick-Kaufman syndrome is a human developmental anomaly syndrome co mprising mesoaxial or postaxial polydactyly, congenital heart disease and hydrometrocolpos, This syndrome is diagnosed most frequently in th e Old Order Amish population and is inherited in an autosomal recessiv e pattern with reduced penetrance and variable expressivity, Homozygos ity mapping and linkage analyses were conducted using two pedigrees de rived from a larger pedigree published in 1978, The PedHunter software query system was used on the Amish Genealogy Database to correct the previous pedigree, derive a minimal pedigree connecting those affected sibships that are in the database and determine the most recent commo n ancestors of the affected persons, Whole genome short tandem repeat polymorphism (STRP) screening showed homozygosity in 20p12, between D2 0S162 and D20S894, an area that includes the Alagille syndrome critica l region, The peak two-point LOD score was 3.33, and the peak three-po int LOD score was 5.21, The physical map of this region has been defin ed, and additional polymorphic markers have been isolated, The region includes several genes and expressed sequence tags (ESTs), including t he jagged1 gene that recently has been shown to be haploinsufficient i n the Alagille syndrome, Sequencing of jagged1 in two unrelated indivi duals affected with McKusick-Kaufman syndrome has not revealed any dis ease-causing mutations.