GENOTYPE/PHENOTYPE CORRELATIONS IN WILLIAMS SYNDROME

描述（改编自申请人的摘要）：威廉姆斯综合症 (WS) 是一种复杂的神经发育障碍，其特征为轻度至 中度智力低下，独特的认知和个性特征， 婴儿高钙血症、面部特征畸形和瓣膜上异常 主动脉瓣狭窄（SVAS）。 这种综合症是由亚微观的 包含弹性蛋白 (ELN) 基因的染色体 7q11.23 缺失。 先前对 WS 和 WS 患者的表型和分子研究 具有 SVAS 的亲属表明 ELN 突变是导致 SVAS 和 WS 中的血管疾病。 由于 WS 是一个连续基因 紊乱，建议目前其他的半合子 未知基因参与精神疾病的发病机制 发育迟缓、独特的认知特征、WS 人格和高钙血症。 表型和基因型变异已开始在 患有 WS 或 SVAS 的受试者。 拟议研究的目标是 表征个体的基因型和表型 7q11.23 的亚显微缺失并识别和表征 可能有助于特定 WS 特征的基因。 有三个 具体目标： 1）确定具有经典 WS 的个体和个体 具有与 WS 重叠的表型特征； 2) 识别并 描述经典 WS 的主要表型特征并使用 这些特征可以表征具有部分 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 认知概况和人格概况）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具体测试；和 人格和适应性行为的测量； 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、识别 来自该区域的新基因的表征，以及对这些基因的测试 参与特定 WS 特征发病机制的基因。 它 预计基因有助于认知特征、个性 将确定 WS 的概况、精神发育迟滞和高钙血症。 本研究的长期目标是提供更好的 了解认知和人格背后的机制 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.