GENOTYPE/PHENOTYPE CORRELATIONS IN WILLIAMS SYNDROME

描述(改编自申请者摘要)：威廉姆斯综合征 WS是一种复杂的神经发育障碍，其特征是轻微到 中度智力障碍，独特的认知和个性特征， 婴儿高钙血症、面部畸形和瓣膜上 主动脉瓣狭窄(SVAS)。这种综合征是由一种亚微观的 包含弹性蛋白(ELN)基因的染色体7q11.23的缺失。 先前对WS和WS患者的表型和分子研究 患有SVAS的家族表明ELN突变是导致 SVAS和WS均有血管病变。因为WS是一个连续的基因 无序，建议目前其他方面的偏向 不明基因参与了精神疾病的发病机制 发育迟缓、独特的认知特征、WS个性和高钙血症。 表型和基因变异性都已开始在 WS或SVAS受试者。拟议研究的目标是 同时表现出基因和表型的特征 7q11.23的亚显微缺失及其鉴定和鉴定 可能影响特定WS特征的基因。一共有三个 具体目标：1)确定具有经典WS的个人和个人 具有与WS重叠的表型特征的人；2)识别和 描述经典WS的主要表型特征并使用 这些特征用来表征部分WS的个体 表型。医学表型的特征将基于 畸形检查，医疗记录审查，以及 超声心动图。神经行为表型(包括两者 认知简档和个性简档)将基于 在旨在测量一般智力的心理测试中， 包括特定认知方面的优势和劣势； 对语言、记忆和视觉空间能力的具体测试；以及 人格和适应行为的测量；以及3)识别基因 负责WS的特定表型特征。遗传分析 将包括WS删除区域的物理映射、标识 以及来自该区域的新基因的特征，并对这些基因进行测试 参与特定WS特征发病机制的基因。它 预计影响认知特征、个性的基因 WS的侧写、智力低下和高钙血症将被识别。 这项研究的长期目标是提供更好的 对认知和人格潜在机制的理解 发展。这项研究的结果将立即用于 医生和提供教育和治疗的从业者 为WS患者及其家人提供的服务。

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.