Genotype/Phenotype Correlations in Williams Syndrome

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Williams syndrome (WS) is a complex neurodevelopmental disorder characterized by mild to moderate mental retardation (MR), a distinctive personality profile, an unusual cognitive profile, infantile hypercalcemia, dysmorphic facial features, and supravalvar aortic stenosis (SVAS). Our research has demonstrated that WS is a contiguous gene disorder resulting from submicroscopic deletions of chromosome 7ql 1.23 including deletion of the elastin gene (causing SVAS, connective tissue abnormalities, and some facial features of WS), the LIM-kinase 1 gene (contributing to the visuospatial constructive cognitive difficulties of WS), and the GTF21 gene (implicated in the reduced general intellectual ability in WS). In addition, we have identified a region of the WS deletion that is likely to include gene(s) that contribute to the WS personality profile. The overall goal of the proposed research is to create a medical and behavioral profile for WS that will then be used to examine genotype/phenotype correlations. We have three specific aims: 1) Ascertain and phenotypically characterize individuals who have WS and individuals who have features that overlap with WS. 2) Identify and characterize the cardinal features of the phenotype of classic WS. The medical phenotype will be characterized based on dysmorphology examination, review of medical records, and echocardiographic analysis. The neurobehavioral phenotype 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 visuospatial abilities; and measures of personality, temperament, and adaptive behavior. 3) Identify genes responsible for specific phenotypic features of WS. Genetic analysis will include defining atypical deletion breakpoints, screening genes in the region for mutations in specific populations (e.g.,GTF21 mutations in nonspecific MR), determining parent of origin and inversion status to investigate the roles of these variables on the phenotype, and testing of candidate genes for involvement in the pathogenesis and phenotypic variability of particular WS features. We expect to identify genes involved in WS personality characteristics and hypercalcemia and to characterize genetic modifying factors. The long term objective is to provide a better understanding of mechanisms underlying cognitive and personality development. The findings will be of immediate use to practitioners who provide educational and therapeutic services to individuals with WS and their families.