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)与自闭症风险增加有关，患病率从25%到50%不等。这意味着大约有超过100的相对风险，这表明FMR1(导致FXS的基因)对自闭症具有相当大的易感性。虽然揭示自闭症病因机制的努力经常被多种未知的病因混淆，但像FXS这样的基因定义的综合征提供了难得的机会，在病因相同的情况下检查基因-大脑-行为的关联。该项目试图通过对遗传风险增加的一级亲属--自闭症患者的亲属和携带FMR1预突变的FXS患者的亲属--的研究，了解FMR1在自闭症症状学中的作用。这个项目建立在我们之前对自闭症和广泛的自闭症表型(BAP)的研究基础上，检查显示与自闭症和BAP共分离的关键的发育、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患者的一级亲属收集的数据进行比较，以确定可能与FMR1相关的跨组潜在重叠图谱。这些分析利用了一个前所未有的机会--从一大群FXS和自闭症患者的家庭中获得儿童语言和认知测试的档案记录。利用这些极具价值的数据，我们将纵向描述自闭症和FXS亲属在学龄期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。表型将被检测与FMR1变异和FMRP的表达有关，FMRP是一种脆性X-智力低下蛋白，缺乏FXS，被认为导致FXS的认知和行为障碍。这项拟议的项目将有助于完善目前对FMR1在自闭症症状学中作用的理解，并进一步表征脆性X预突变的表型。 公共卫生相关性：该项目旨在确定自闭症遗传易感性的特定发育和认知语言标记，该标记可能与FMR1相关，该基因导致脆性X综合征(FXS)，并被假设在自闭症症状学中发挥作用。这个项目将通过对遗传易感性增加的一级亲属(对于FXS，他们是FMR1预突变的携带者)进行跨人群比较来检查新的纵向发育表型，以阐明自闭症和FXS的重叠，并调查亲属中可能与该候选基因变异有关的亚临床特征。旨在揭示自闭症及其与FXS重叠的发病机制的研究可能会导致循证预防或治疗方法。

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.