A Family-Genetic Study of Autism and Fragile X Syndrome

 描述(申请人提供)：本修订申请的父母R01旨在通过对遗传易感性增加的一级亲属-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，告知FMR1相关分子变异在自闭症症状学中的作用。该建议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，以检查显示与自闭症和BAP共分离的关键发育、临床、语言和社会认知表型。我们正在对照从自闭症患者的一级亲属那里收集的数据，检查前突变携带者中的这些表型，以确定潜在的跨组重叠图谱，这可能与FMR1相关的分子变异有关。最初的提案还利用了一个史无前例的机会--可获得儿童语言档案和来自 一大群患有FXS和自闭症的家庭。该项目取得了强劲而稳定的进展，与此同时，一项附带拨款也产生了一些重要的发现，重点是确定自闭症和BAP中具有遗传意义的语言特征。我们在一部作品中试用了这些措施，并可能与自主唤醒有关。随着专家合作者小组的扩大，预突变携带者小组取得了令人兴奋的结果。在这一修订申请中，我们提出了一系列工具来分析语篇产生，借鉴了心理语言学和计算语言学中已经开发的技术，初步数据表明，这些工具可能会捕捉到BAP和FMR1预突变中与语言相关的重要特征。这些工具提供了语篇关键词汇和语义特征的量化测量，并使用眼球跟踪提供了关于语言处理如何与语篇中的感知和注意联系起来的新信息，我们相信，这些新的语言测量方法的添加将大大提高我们现有数据的价值，并加深我们对FMR1，更具体地说，FMRP在自闭症症状学中的作用的理解，以及进一步表征FMR1预突变的表型。

 DESCRIPTION (provided by applicant): The parent R01 for this revision application was intended to inform the role of FMR1-related molecular variation 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. The proposal built 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 are examining these phenotypes among premutation 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-related molecular variation. The original proposal also capitalized 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. The project has proceeded strongly and steadily, while at the same time a number of important findings have emerged from a companion grant focused on identifying genetically meaningful language features in autism and the BAP. We piloted these measures in a production, and potentially related to autonomic arousal. With an expanded team of expert collaborators subgroup of premutation carriers, with exciting results. In this revision application we propose a battery of tools for analyzing discours production, drawing on techniques that have been developed in psycholinguistics and computational linguistics, and which Preliminary Data suggest may capture important language-related profiles in the BAP and the FMR1 premutation. These tools provide quantitative measures of key lexical and semantic features of discourse, as well as using eye tracking to provide new information on how language processing is linked to perception and attention during discourse included, we believe that the addition of these novel measures of language will substantially enhance the value of our existing data, and sharpen our understanding of the role of FMR1, and FMRP more specifically, in autism symptomatology, as well as further characterize the phenotype of the FMR1 premutation.