Genotype/Phenotype Correlations in Williams Syndrome

描述（由申请人提供）：威廉姆斯综合征（WS）是一种复杂的神经发育障碍，其特征为轻度至中度智力迟钝（MR）、独特的人格特征、不寻常的认知特征、婴儿高钙血症、畸形的面部特征和瓣上主动脉狭窄（SVAS）。我们的研究表明，WS是一种由染色体7ql 1.23亚显微缺失引起的连续基因疾病，包括弹性蛋白基因的缺失（导致SVAS、结缔组织异常和WS的一些面部特征）、limk激酶1基因的缺失（导致WS的视觉空间建构性认知困难）和GTF21基因的缺失（涉及WS的一般智力能力降低）。此外，我们已经确定了WS缺失的一个区域，该区域可能包括导致WS人格特征的基因。拟议研究的总体目标是创建WS的医学和行为概况，然后用于检查基因型/表型相关性。我们有三个具体目标：1)确定WS患者和与WS有重叠特征的患者的表型特征。2)鉴定和表征经典WS表型的主要特征。医学表型将根据畸形检查、病历回顾和超声心动图分析来确定。神经行为表现型的特征将基于旨在测量一般智力的心理测试，包括认知特定方面的优势和劣势；语言、记忆和视觉空间能力的特定测试；以及个性，气质和适应性行为的测量。3)确定与WS特异性表型特征相关的基因。遗传分析将包括定义非典型缺失断点，在特定人群中筛选该区域的突变基因（例如，非特异性MR中的GTF21突变），确定亲本起源和反转状态，以研究这些变量对表型的作用，以及测试参与特定WS特征的发病机制和表型变异性的候选基因。我们期望确定与WS人格特征和高钙血症有关的基因，并确定遗传修饰因素的特征。长期目标是提供对认知和人格发展机制的更好理解。研究结果将立即用于为WS患者及其家庭提供教育和治疗服务的从业人员。

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.