A Family-Genetic Study of Autism and Fragile X Syndrome

摘要 脆性X综合征(FXS)与自闭症谱系障碍(ASD)的风险增加有关， 患病率在~40-74%1-6之间，提示FMR1基因(导致FXS的基因)和它的 脆性X智力低下蛋白(FMRP)是ASD的重要危险因素 症状学。重要的是，与自闭症相关的特征(即广泛的自闭症表型，或BAP)也 在FMR1前突变携带者(PM携带者)中观察到较高的发生率，提供了进一步的证据 FMR1相关变异在ASD相关表型中的作用。在最初的资金期内，这个项目 确定了一些临床、心理语言学和社会认知特征，这些特征可以作为候选 内表型(即与一种疾病相关的可遗传性状，在患病和未患病人群中可测量 个体)ASD和FXS重叠，这在一级亲属中也很明显 遗传责任(对于FXS，PM承运人)。在这份修订后的续订申请中，我们建立在以下基础之上 语用语言领域的深层次行为和神经表型研究结果令人振奋 我们已经证明ASD和FMR1突变(PM携带者和FXS)的特征有很强的重叠。在……里面 具体地说，我们采用多种方法评估韵律(例如，语调、重音和语言节奏)， 这是一种关键的语用技能，在自闭症患者中受到损害(并与社会障碍有关)，而且 在BAP中受到影响的未受影响的亲属。分析包括来自三个独立队列的数据 大量现有数据可用于计算和数据驱动分析，以识别表型定义 可能跨越诊断边界并提供线索的同质亚群 可以为病因学和治疗研究提供信息。初步数据表明，这些语用和韵律 轮廓与语音的神经处理有关，在神经中有明显的差异 频率跟随响应(FFR)。FFR是频谱和时间编码的精确神经索引 中脑内的声音，作为快速听觉处理的晴雨表，与表现力有关 以及终生接受的演讲和与语言相关的技能。FMRP在细胞中高度表达 听觉中脑，使我们专注于中脑内语音的频谱和时间编码 作为与FMR1连锁的神经标记物，与FMR1的发病机制相关的候选尤其强烈 ASD中的语言相关功能。在此续订申请中，我们将调查FFR以及多个 PM携带者中韵律的语境评估(利用来自三个独立队列的数据并应用 跨不同对话上下文的韵律的复杂计算建模)以检测关键的ASD- 与FMR1相关变异相关的语用和神经表型，具有显著的 阐明ASD的发病机制，告知治疗。

Abstract Fragile X syndrome (FXS) is associated with an increased risk of autism spectrum disorder (ASD), with prevalence rates ranging from ~40-74%1-6, suggesting that the FMR1 gene (the gene causing FXS) and its protein product, the Fragile X Mental Retardation Protein (FMRP), constitute a highly important risk for ASD symptomatology. Importantly, ASD-related features (i.e., the broad autism phenotype, or BAP) have also been observed at elevated rates among carriers of the FMR1 premutation (PM carriers), providing further evidence of the role of FMR1-related variation in ASD-related phenotypes. In the original period of funding, this project identified a number of clinical, psycholinguistic, and social-cognitive features that may serve as candidate endophenotypes (i.e., heritable traits associated with a disease and measurable in affected and unaffected individuals) overlapping in ASD and FXS, which were also evident among first-degree relatives at increased genetic liability (and in the case of FXS, PM carriers). In this revised renewal application, we build on these promising findings with deep behavioral and neural phenotyping in the domain of pragmatic language (where we have demonstrated robust overlap in profiles in ASD and FMR1 mutations (PM carriers and FXS). In particular, we apply multi-method assessments of prosody (e.g., intonation, stress, and rhythm of language), which is a critical pragmatic skill that is impaired in ASD (and linked with social impairments), and also impacted in the BAP in unaffected relatives. Analyses include data from three independent cohorts with extensive existing data available for computational and data-driven analyses to identify phenotypically-defined homogeneous subgroups that may cross diagnostic borders and provide clues to biological mechanisms that can inform studies of etiology and treatment. Preliminary data suggest that these pragmatic and prosodic profiles are associated with the neural processing of speech sounds, with robust differences in the neural frequency following response (FFR). The FFR is a precise neural index of spectral and temporal encoding of sound within the midbrain, that serves as a barometer of rapid auditory processing that is linked to expressive and receptive speech and language-related skills throughout the lifespan7-13. FMRP is highly expressed in the auditory midbrain, making our focus on the spectral and temporal encoding of speech within the midbrain a particularly strong candidate as a neural marker linked with FMR1, and relevant to the pathogenesis of language-related features in ASD. In this renewal application, we investigate the FFR together with a multi- context assessment of prosody in PM carriers (leveraging data from three independent cohorts and applying sophisticated computational modeling of prosody across different conversational contexts) to detect key ASD- related pragmatic and neural phenotypes linked with FMR1-related variation that have significant potential to illuminate the pathogenesis of ASD and inform treatment.