A Family-Genetic Study of Autism and Fragile X Syndrome

自闭症和脆性 X 综合征的家族遗传学研究

• 批准号: 8238493
• 负责人: Molly C Losh
• 金额: $ 75.14万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8238493
• 关键词: Affect; Age-Years; Archives; Autistic Disorder; Candidate Disease Gene; Characteristics; Child; Childhood; Clinical; Cognitive; Data; Development; Etiology; FMR1; FMR1 Gene; FMR1 Premutation; FMRP; Family; Fragile X Mental Retardation Protein; Fragile X Premutation; Fragile X Syndrome; Genes; Genetic; Genetic Markers; Growth; Impaired cognition; Individual; Intervention; Language; Lead; Linguistics; Link; Measures; Mediating; Molecular; Molecular Genetics; Mutation; Outcome; Parents; Pathogenesis; Phenotype; Play; Population; Prevalence; Prevention approach; Proteins; Records; Relative (related person); Relative Risks; Research; Resources; Risk; Role; School-Age Population; Siblings; Source; Staging; Susceptibility Gene; Syndrome; Testing; Translating; Variant; Work; behavioral impairment; brain behavior; cohort; evidence base; family genetics; insight; novel; social

DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is associated with an increased risk of autism, with prevalence rates ranging from 25-50%. This translates to an approximate relative risk of over 100, indicating that FMR1 (the gene causing FXS) confers considerable vulnerability to autism. While efforts to uncover the causal mechanisms in autism are often confounded by multiple unknown etiologies, genetically defined syndromes such as FXS provide the rare opportunity to examine gene-brain-behavior associations in an etiologically homogeneous condition. This project is an attempt to inform the role of FMR1 in autism symptomatology through the study of 1st degree relatives who are at increased genetic liability - relatives of individuals with autism and relatives of individuals with FXS, who are carriers of the FMR1 premutation. This project builds on our prior studies of autism and the broad autism phenotype (BAP), to examine key developmental, clinical, language, and social cognitive phenotypes shown to cosegregate with autism and the BAP. We propose to examine these phenotypes among FXS carriers in comparison to data collected from 1st degree relatives of individuals with autism, to identify potentially overlapping profiles across groups, which may be linked to FMR1. These analyses capitalize on an unprecedented opportunity -- the availability of archival childhood language and cognitive testing records from a large cohort of families of individuals with FXS and autism. Using these highly valuable data, we will characterize longitudinally the language and cognitive development of autism and FXS relatives over the early school-age years, and examine downstream outcomes across clinical, language, and social cognitive domains. Phenotypes will be examined in relation to FMR1 variation and expression of FMRP, the fragile X-mental retardation protein that is deficient in FXS and is believed to cause the cognitive and behavioral impairments in FXS. The proposed project will help to refine current understanding of the role of FMR1 in autism symptomatology, and further characterize the phenotype of the fragile X premutation. PUBLIC HEALTH RELEVANCE: This project aims to identify specific developmental and cognitive-linguistic markers of genetic liability to autism which may be associated with FMR1, the gene that causes fragile X syndrome (FXS), and which is hypothesized to play a role in autism symptomatology. This project will examine novel longitudinal developmental phenotypes in a cross-population comparison of 1st degree relatives who are at increased genetic liability (and in the case of FXS, who are carriers of the FMR1 premutation), to illuminate the overlap of autism and FXS and investigate subclinical features among relatives which could be related to variation in this candidate gene. Research aimed at uncovering the pathogenesis of autism and its overlap with FXS may lead to evidence-based approaches to prevention or treatment.

描述（由申请人提供）：脆性X综合征（FXS）与自闭症风险增加有关，患病率在25-50%之间。这转化为大约超过100的相对风险，表明FMR1（导致FXS的基因）对自闭症具有相当大的脆弱性。虽然发现自闭症的因果机制的努力经常被多种未知的病因所混淆，但遗传定义的综合征（如FXS）提供了在病因同质条件下检查基因-脑-行为关联的难得机会。本项目试图通过研究遗传倾向增加的一级亲属——自闭症患者的亲属和FXS患者的亲属，这些人都是FMR1前兆突变的携带者，来了解FMR1在自闭症症状学中的作用。该项目建立在我们之前对自闭症和广泛自闭症表型（BAP）的研究基础上，研究与自闭症和BAP共分离的关键发育、临床、语言和社会认知表型。我们建议将FXS携带者的这些表型与从自闭症个体的一级亲属收集的数据进行比较，以确定可能与FMR1相关的群体间潜在的重叠特征。这些分析利用了一个前所未有的机会——来自一大群FXS和自闭症患者家庭的儿童语言和认知测试档案记录。利用这些非常有价值的数据，我们将纵向描述自闭症和FXS亲属在早期学龄期的语言和认知发展，并检查临床、语言和社会认知领域的下游结果。我们将研究表型与FMR1变异和FMRP表达的关系。FMRP是脆性x -智力迟钝蛋白，在FXS中缺乏，被认为会导致FXS的认知和行为障碍。拟议的项目将有助于完善目前对FMR1在自闭症症状学中的作用的理解，并进一步表征脆性X前兆突变的表型。