Genotype/Phenotype Correlations in Williams Syndrome

威廉姆斯综合征的基因型/表型相关性

• 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
• 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

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，其特征是轻度至中度智力低下（MR），独特的人格特征，异常的认知特征，婴儿高钙质，畸形型面部特征，以及肩部主动脉膨胀（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 （与WS中的一般智力能力降低有关）。此外，我们已经确定了WS缺失的一个区域，该区域可能包括有助于WS人格概况的基因。拟议的研究的总体目标是为WS创建医学和行为概况，然后将其用于检查基因型/表型相关性。我们有三个特定的目标：1）确定和表型表征具有与WS重叠的WS和个体的个人。 2）识别并表征经典WS表型的基本特征。医疗表型将根据畸形检查，医疗记录审查和超声心动图分析来表征。神经行为表型将根据旨在衡量一般智力的心理测试进行表征，包括认知的特定方面的优点和劣势；语言，记忆和视觉空间能力的特定测试；以及人格，气质和适应性行为的度量。 3）确定负责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裂点，在该区域中筛选基因特定种群中的突变（例如，非特异性MR中的GTF21突变），确定原点和反转状态的父母，以研究这些变量在候选基因中的作用，以及在病因和现象中的参与性的特定性和现象型的参与。我们期望确定与WS人格特征和高钙血症有关的基因，并表征遗传修饰因素。长期目标是对认知和人格发展的基础机制提供更好的理解。这些发现将立即用于为WS及其家人提供教育和治疗服务的从业人员。