GENOTYPE/PHENOTYPE CORRELATIONS IN WILLIAMS SYNDROME

描述（改编自申请人的摘要）：威廉姆斯综合征 (WS)是一种复杂的神经发育障碍， 中度智力迟钝，独特的认知和个性特征， 婴儿高钙血症，畸形的面部特征，和瓣膜上 主动脉瓣狭窄（SVAS）。 这种综合症是由一种亚显微的 染色体7q11.23缺失，其中包含弹性蛋白（ELN）基因。 先前对WS患者的表型和分子研究， SVAS的激酶活性表明ELN突变是导致 由于WS是一个连续的基因， 疾病，它提出，目前其他半合子 一个未知的基因参与了精神分裂症的发病机制， 发育迟缓、独特的认知特征、WS人格和高钙血症。 表型和基因型的变异性已经开始被确定， WS或SVAS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，并鉴定和表征 可能导致特定WS特征的基因。 有三 具体目标：1）确定具有典型WS的个体和个体 具有与WS重叠的表型特征的人; 2）识别和 描述典型WS的主要表型特征， 这些特征来表征具有部分WS的个体 表型 医学表型将根据以下方面进行表征： 畸形学检查，病历审查，以及 超声心动图 神经行为表型（包括 认知概况和个性概况）将基于 在旨在测量一般智力的心理测试中， 包括在认知的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;以及 人格和适应行为的措施; 3）识别基因 遗传分析是导致WS的特定表型特征的主要原因。 将包括WS缺失区的物理作图、鉴定 和表征来自该区域的新基因，并测试这些 参与特定WS特征的发病机制的基因。 它 预计影响认知能力、个性、 将确定WS的特征、精神发育迟滞和高钙血症。 这项研究的长期目标是提供一个更好的 理解认知和人格的潜在机制 发展 这项研究的结果将立即用于 提供教育和治疗的医生和从业者 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.