Project Summary Pragmatic (i.e., social) language impairments are a defining feature of autism spectrum disorder (ASD) that impose a significant burden on individuals throughout their lifespan. Strong evidence suggests that pragmatic language differences aggregate subclinically among first-degree relatives, reflecting the broad autism phenotype (BAP), and have been linked to variation in FMR1, a highly penetrant ASD risk gene that causes fragile X syndrome (FXS) and a constellation of clinical and neuropsychological phenotypes among women who carry the FMR1 gene in its premutation (PM) state. In the prior award period, we demonstrated striking parallels in pragmatic-related skills in the BAP and FMR1 PM, as well as important phenotypic distinctions, which together point toward highly specific ASD-related skills that appear tied to the FMR1 gene. In this renewal application, we build on this work with an expanded, multidisciplinary team of investigators to apply innovative multi-layered deep behavioral and neural phenotyping, building on our most promising findings, with an armamentarium of cutting-edge, computationally-based analytic platforms to further delineate the mechanistic contributors to ASD- related pragmatic profiles in individuals with FMR1 mutations (fragile X syndrome and the FMR1 premutation). Delineating the molecular genetic underpinnings of ASD-related pragmatic skills is crucial for understanding the etiology of the social communication clinical symptom domain of ASD, which may reveal biologically based targets for intervention. In this project, we will characterize ASD-related pragmatic profiles that extend beyond traditional, categorically defined diagnostic boundaries among individuals with FMR1 mutations, and how such profiles may be linked with targeted neurophysiological signatures and molecular genetic variation. This project will capitalize on extensive, comparable data collected from individuals with ASD and parents with and without the broad autism phenotype (BAP), available through an active companion R01. Aim 1 will apply both hypothesis- and data-driven analytic approaches to a comprehensive battery assessing component skills contributing to ASD-related pragmatic profiles in individuals with an FMR1 mutation. Aim 2 will employ a battery of targeted, multidimensional electrophysiological measures to examine potential neural correlates of pragmatic profiles. Finally, Aim 3 will evaluate the relationship between behavioral and neural phenotypic signatures obtained in Aims 1 and 2 and FMR1-related genetic variation. Results from the prior phase of this project and new preliminary data strongly implicate a complex network of skills contributing to ASD-related pragmatic profiles among individuals with a FMR1 mutation that may be sensitively measured with the advanced fine-grained computational- and machine-learning-based approaches proposed, with compelling ties to neurophysiological and molecular genetic correlates that ...