LINKAGE STUDIES OF WAARDENBURG SYNDROME

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It has been known for many years that deafness aggregates in families, and that this familial aggregation is often due to a genetic disorder. Genetically based deafness is often syndromic in nature. That is, a consistent repertoire of associated morphological signs and symptoms cosegregates through families with liability to deafness. Several deafness syndromes appear to be caused by single genes that exert a major effect, and that are clearly inherited via either dominant or recessive modes of transmission with high penetrance. Recent advances in molecular biology and statistical approaches to linkage analysis now provide us, for the first time, with the techniques to rigorously evaluate this claim, and to progress towards understanding the biochemical ad physiological mechanisms underlying genetically transmitted forms of deafness. This is a proposal to: i.) ascertain a large number of multiplex Waardenburg syndrome pedigrees, a type of genetic deafness transmitted via an autosomal dominant major locus with high penetrance; and ii.) to conduct linkage analyses on these pedigrees using the abundant, highly polymorphic DNA markers that have recently become available to span virtually the entire human genome. The proposal seeks to capitalize on resources uniquely available through the longstanding collaboration between researchers and clinicians at the Medical College of Virginia and Gallaudet University. These resources include broad prior experience communicating with members of the deaf community via sign language and teletype terminals, the availability of an established annual survey instrument suitable for identifying many new families, coupled with extensive research experience in implementing precise diagnostic criteria, conducting the cell culture and molecular biological laboratory procedures necessary to genotype a very large number of highly polymorphic DNA markers, and performing sensitive and powerful statistical analyses. Genotyping of markers will first focus on areas where previous studies suggest a gene for Waardenburg syndrome might be located. Several statistical approaches will be applied to the data in order to fully utilize their potential. Any strong positive findings will be pursued by cloning additional markers from that part of the genome where a major locus for Waardenburg syndrome might lie in order to map its location more precisely to facilitate its eventual cloning and sequencing.