Project Summary Impaired pragmatic (i.e., social) language is a defining symptom domain of autism spectrum disorder (ASD) and imposes significant burden on affected individuals and their families throughout the lifespan. A wealth of evidence demonstrates that pragmatic abilities are highly heritable and are a primary feature of the broad autism phenotype (BAP) seen in unaffected relatives of autistic individuals. Further, pragmatic language differences that mirror those in ASD and the BAP are observed in carriers of FMR1 mutation conditions (e.g., fragile X syndrome and the FMR1 premutation), implicating this high confidence ASD risk gene in the ASD pragmatic phenotype. In addition to being valuable targets for intervention, pragmatic language abilities also appear to be sensitive to genetic liability to ASD, and so can provide a window into the biological origins of ASD symptomology. Extensive evidence from our prior work and current NIMH-funded R01 (R01MH091131) has reported overlapping profiles of impaired pragmatic language and related molecular-genetic and neurobiological correlates in ASD and in FMR1 mutation carriers. In this project, we advance this work by investigating the mechanistic origins of these differences, with a focus on motor-speech abilities shown to be disrupted in ASD and the BAP which are related to pragmatic language skills, in carriers of the FMR1 premutation (PM), to illuminate gene-brain-behavior pathways associated with this core ASD symptom domain. Preliminary data show robust differences in motor- speech skills among PM carriers that are qualitatively similar to those observed in ASD and the BAP, and which relate to high-order pragmatic-related abilities and neurobiological and molecular-genetic variation. Specifically, Aim 1 characterizes the motor-speech skills that contribute to ASD-related pragmatic profiles in PM carriers through a targeted battery of assessments indexing mechanistic contributors to pragmatic language including speech articulation, audio-motor synchronization, rhythmic speech fluency, and auditory feedback control. Aim 2 examines associations between targeted motor-speech skills and profiles of core, high-order pragmatic abilities in PM carriers. Finally, Aim 3 investigates both neural and molecular-genetic influences on motor-speech skills and their relationship to broader ASD-related pragmatic profiles in PM carriers. Together, these aims will inform the complex relationships between neurobiological and genetic markers, motor-speech mechanisms, and ASD- associated pragmatic abilities that may be linked with FMR1-related variation. This theoretically driven, targeted, and efficient study design will leverage rich and extensive existing data to uniquely reveal mechanistic and biological origins of this significant ASD clinical symptom domain. Findings from this work may hold important clinical-translational implications for the ASD and FMR1 communities, informing mechanistic intervention target...