GENOTYPE/PHENOTYPE CORRELATIONS IN WILLIAMS SYNDROME

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DESCRIPTION (Adapted from the Applicant's Abstract): Williams Syndrome (WS) is a complex neurodevelopmental disorder characterized by mild to moderate mental retardation, unique cognitive and personality profiles, infantile hypercalcemia, dysmorphic facial features, and supravalvular aortic stenosis (SVAS). This syndrome is caused by a submicroscopic deletion of chromosome 7q11.23 which encompasses the elastin (ELN) gene. Previous phenotypic and molecular studies of individuals with WS and kindreds with SVAS indicate that ELN mutations are responsible for vascular disease in both SVAS and WS. Since WS is a contiguous gene disorder, it is proposed that hemizygosity of other currently unidentified genes is involved in the pathogenesis of the mental retardation, unique cognitive profile, WS personality, and hypercalcemia. Both phenotypic and genotypic variability have begun to be identified in subjects with WS or SVAS. The goal of the proposed research is to characterize both the genotype and the phenotype of individuals with submicroscopic deletions of 7q11.23 and to identify and characterize genes that may contribute to specific WS features. There are three specific aims: 1) Ascertain individuals with classic WS and individuals who have phenotypic features that overlap with WS; 2) Identify and characterize the cardinal phenotypic features of classic WS and use these features to characterize individuals with the partial WS phenotype. The medical phenotype will be characterized based on dysmorphology examination, review of medical records, and echocardiography. The neurobehavioral phenotype (including both cognitive profile and personality profile) will be characterized based on psychological tests designed to measure general intelligence, including strengths and weaknesses in particular aspects of cognition; specific tests of language, memory, and visuo-spatial abilities; and measures of personality and adaptive behavior; and 3) Identify genes responsible for specific phenotype features of WS. Genetic analysis will include physical mapping of the WS deletion region, identification and characterization of new genes from this region, and testing of these genes for involvement in the pathogenesis of particular WS features. It is expected that genes contributing to the cognitive profile, personality profile, mental retardation, and hypercalcemia of WS will be identified. The long term objective of this research is to provide a better understanding of mechanisms underlying cognitive and personality development. The findings of this research will be of immediate use to physicians and to practitioners who provide educational and therapeutic services to individuals with WS and their families.