A Family-Genetic Study of Language in Autism

项目摘要 务实（即，社交）语言缺陷是自闭症谱系障碍（ASD）的一个定义特征， 在整个生命周期中对个人造成重大负担。有力的证据也表明，这种临床 结构域受未受影响亲属中ASD遗传易感性的影响，构成了ASD的主要组成部分。 广泛的自闭症表型（BAP），并与未受影响的亲属中ASD的多基因风险增加有关。 ASD的语用语言特征也与FMR 1携带者的表型有明显重叠 突变，暗示这一高度外显的ASD风险基因在ASD的实用语言表型， 特别的。因此，语用语言域不仅在ASD中具有高度的临床意义，而且 对潜在的ASD遗传易感性敏感，使这种技能成为了解生物学特性的重要目标。 ASD的起源及其组成特征，具有潜在的重要临床应用。在这场竞争中， 更新，我们将应用创新的深度表型分析方法和互补的分析设备， 平台来剖析ASD中语用语言障碍的贡献者及其生物学基础。使用 一项家庭研究设计，包括一个代表性的ASD队列，为女孩、ASD父母和相应的 对照组，我们将表征ASD相关的语用概况，超越传统的，明确的- 明确的诊断界限，这可能与不同的神经信号和分子遗传学有关。 变化量目标1将应用假设和数据驱动的分析方法来分析一个全面的 电池评估组件的技能，有助于语用障碍的ASD，亚临床语用 父母之间的差异。目标2将采用一系列有针对性的电生理措施， 检查ASD和BAP中语用障碍的潜在神经相关性。目标3将评估 分别在目的1和2中获得的行为和神经表型特征之间的关系， FMR 1相关的遗传变异。我们的初步研究显示了一个复杂的技能网络 有助于ASD中的语用障碍，这可以用高级细粒度 在这个项目中提出的基于计算和机器学习的方法，具有令人信服的联系， 神经生理学和分子遗传学的相关性，将在这个项目中进行测量。在一起，富人和 所产生的广泛数据将有助于理解有助于实现 ASD的异质性，以及这一重要临床领域的机制和生物学起源。我们的研究结果 将使我们更接近实现我们的长期转化目标：促进我们对 ASD中的语用语言障碍，以提高临床结果的预测和帮助指导 ASD的未来干预和治疗。

Project Summary Pragmatic (i.e., social) language deficits are a defining feature of autism spectrum disorder (ASD), which can impose significant burden on individuals throughout the lifespan. Strong evidence also suggests that this clinical domain is influenced by genetic liability to ASD in unaffected relatives, constituting a principal component of the broad autism phenotype (BAP) and linked with increased polygenic risk for ASD in unaffected relatives. Pragmatic language features of ASD also show significant overlap with phenotypes observed in carriers of FMR1 mutations, implicating this highly penetrant ASD risk gene in the pragmatic language phenotype of ASD in particular. The pragmatic language domain is therefore not only highly clinically significant in ASD, but also sensitive to underlying ASD genetic liability, making this skill an important target for understanding the biological origins of ASD and its component features, with potentially important clinical applications. In this competing renewal, we will apply innovative deep phenotyping methods and an armamentarium of complementary analytic platforms to dissect the contributors to pragmatic language impairments in ASD and their biological basis. Using a family-study design and including a representative ASD cohort enriched for girls, ASD parents, and respective control groups, we will characterize ASD-related pragmatic profiles that extend beyond traditional, categorically- defined diagnostic boundaries, which may be linked with distinct neural signatures and molecular genetic variation. Aim 1 will apply both hypothesis- and data-driven analytic approaches to analyze a comprehensive battery assessing component skills contributing to pragmatic impairments in ASD, and subclinical pragmatic differences in the BAP among parents. Aim 2 will employ a battery of targeted electrophysiological measures to examine potential neural correlates of pragmatic impairment in ASD and the BAP. Finally, Aim 3 will evaluate the relationship between behavioral and neural phenotypic signatures obtained in Aims 1 and 2, respectively, and FMR1-related genetic variation. Our preliminary studies demonstrated a complex network of skills contributing to pragmatic impairments in ASD that may be sensitively measured with the advanced fine-grained computational- and machine-learning-based approaches proposed in this project, with compelling ties to neurophysiological and molecular genetic correlates that will be measured in this project. Together, the rich and extensive data produced will contribute to the understanding of the fine-grained skills that contribute to the heterogeneity in ASD, and the mechanistic and biological origins of this important clinical domain. Our findings will move us closer to achieving our long-term translational goal: to advance our understanding of the causes of the pragmatic language impairment in ASD in order to improve prediction of clinical outcomes and help guide future interventions and treatment in ASD.