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， 患病率范围为~40-74%1-6，表明FMR 1基因（引起FXS的基因）及其 脆性X智力迟钝蛋白（FMRP）是一种蛋白质产物，对ASD构成了高度重要的风险 医学。重要的是，ASD相关特征（即，广泛自闭症表型，或BAP）也已被 观察到FMR 1前突变携带者（PM携带者）的发病率升高，提供了进一步的证据 FMR 1相关变异在ASD相关表型中的作用。在最初的资助期内，该项目 确定了一些临床，心理语言学和社会认知特征，可以作为候选人 内表型（即，与疾病相关的遗传特征，可在患病和未患病者中测量 个体）在ASD和FXS中重叠，这在一级亲属中也很明显， 遗传责任（以及FXS、PM携带者）。在此修订后的更新应用程序中，我们建立在这些 在语用语言领域（其中 我们已经证明了ASD和FMR 1突变（PM携带者和FXS）的谱的强重叠。在 特别地，我们应用韵律的多方法评估（例如，语调、重音和语言节奏）， 这是一种重要的语用技能，在ASD中受损（并与社交障碍有关）， 未受影响的亲属的BAP受到影响。分析包括来自三个独立队列的数据， 广泛的现有数据可用于计算和数据驱动的分析，以确定表型定义的 可能跨越诊断边界的同质亚组，并为生物学机制提供线索， 可以为病因学和治疗的研究提供信息。初步数据表明，这些语用和韵律 简档与语音的神经处理相关，在神经处理中具有鲁棒差异。 频率跟随反应（FFR）。血流储备分数是一个精确的神经指标的频谱和时间编码， 中脑内的声音，作为快速听觉处理的晴雨表，与表达有关。 和接受性言语和语言相关技能贯穿整个生命周期7 -13。FMRP高表达于 听觉中脑，使我们的重点放在频谱和时间编码的语音在中脑， 作为与FMR 1相关的神经标记物的特别强的候选者，并且与以下的发病机制相关： ASD中的语言相关功能。在此更新应用中，我们研究FFR以及多个 PM载体中韵律的上下文评估（利用来自三个独立队列的数据并应用 跨不同会话上下文的韵律的复杂计算建模）来检测关键ASD- 与FMR 1相关变异相关的语用和神经表型，具有显著的潜力， 阐明ASD的发病机制并指导治疗。

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.