Genotype/Phenotype Correlations in Williams Syndrome

威廉姆斯综合征的基因型/表型相关性

基本信息

批准号：
7219512
负责人：
CAROLYN B. MERVIS
金额：
$ 127.93万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-05-17 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7219512
关键词：
Adaptive Behaviors Affect Aortic Valve Stenosis Behavior Behavioral Biological Assay Candidate Disease Gene Cardiovascular Surgical Procedures Characteristics Chromosome Deletion Chromosomes Clinical Cognition Cognitive Complex Connective Tissue Correlation Studies Development Disease Dysmorphology Echocardiography Elastin Equilibrium Face Family Fluorescent in Situ Hybridization Foundations Gene Deletion Gene Expression Gene-Modified General Population Genes Genetic Genotype Goals Grant Hypercalcemia Hypertension Individual Infantile hypercalcemia Intelligence LIM Domain Kinase 1 Language Tests Lead Location Maps Measurement Measures Medical Medical Records Memory Mental Retardation Moderate Mental Retardation Modification Mutation Neurodevelopmental Disorder Other Genetics Parents Pathogenesis Personality Personality Development Phenotype Physiology Play Point Mutation Population Psychological Tests Reporting Research Role Sampling Screening procedure Services Temperament Testing Therapeutic Visuospatial Williams Syndrome base chromosome mutation design genetic analysis insight instrument interest neurobehavioral research study success trait

项目摘要

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.

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低下（MR）、独特的个性特征、不寻常的认知特征、婴儿期高钙血症、畸形面部特征和瓣上主动脉瓣狭窄（ SVAS）。我们的研究表明，WS 是一种连续基因疾病，由 7ql 1.23 染色体亚显微缺失引起，包括弹性蛋白基因缺失（导致 SVAS、结缔组织异常和 WS 的一些面部特征）、LIM 激酶 1 基因（有助于WS 的视觉空间建构性认知困难）和 GTF21 基因（与 WS 的一般智力能力下降有关）。此外，我们还确定了 WS 缺失的一个区域，该区域可能包含有助于 WS 性格特征的基因。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) 确定患有 WS 的个体以及具有与 WS 重叠特征的个体并对其进行表型表征。 2) 识别并描述经典 WS 表型的主要特征。将根据畸形检查、病历审查和超声心动图分析来表征医学表型。神经行为表型将根据旨在测量一般智力的心理测试来表征，包括特定认知方面的优势和劣势；语言、记忆和视觉空间能力的具体测试；以及人格、气质和适应性行为的测量。 3) 鉴定负责 WS 特定表型特征的基因。遗传分析将包括定义非典型缺失断点、筛选该区域中特定群体突变的基因（例如，非特异性 MR 中的 GTF21 突变）、确定亲本来源和倒位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的候选基因。我们期望识别与 WS 人格特征和高钙血症有关的基因，并描述遗传修饰因素的特征。长期目标是更好地理解认知和人格发展的机制。研究结果将立即可供为 WS 患者及其家人提供教育和治疗服务的从业者使用。