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 interventi...