A Family-Genetic Study of Autism and Fragile X Syndrome

描述（由申请人提供）：脆性X综合征（FXS）与自闭症风险增加相关，患病率范围为25- 50%。这意味着大约超过100的相对风险，表明FMR 1（导致FXS的基因）赋予自闭症相当大的脆弱性。虽然揭示自闭症因果机制的努力经常被多种未知病因所混淆，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-大脑-行为关联的难得机会。 该项目试图通过研究遗传易感性增加的一级亲属（自闭症患者的亲属和FXS患者的亲属，他们是FMR 1前突变的携带者）来了解FMR 1在自闭症症状中的作用。该项目建立在我们先前对自闭症和广泛自闭症表型（BAP）的研究基础上，以检查与自闭症和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携带者中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FMR 1相关的跨组潜在重叠的特征。这些分析利用了一个前所未有的机会--从一个由FXS和自闭症患者组成的大型家庭中获得档案儿童语言和认知测试记录。使用这些非常有价值的数据，我们将纵向描述自闭症和FXS亲属在学龄早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。将检查与FMR 1变异和FMRP表达相关的表型，FMRP是FXS缺陷的脆性X-智力低下蛋白，被认为会导致FXS中的认知和行为障碍。拟议的项目将有助于完善目前对FMR 1在自闭症中的作用的理解，并进一步表征脆性X前突变的表型。

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.