A Family-Genetic Study of Autism and Fragile X Syndrome

Fragile X syndrome (FXS) is associated with an increased risk of autism spectrum disorder (ASD), with prevalence rates ranging from ~25-50% (13-17), 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 have also been observed at elevated rates among carriers of the FMR1 premutation, 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 behavioral, developmental, and neuropsychological 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, who are carriers of the FMR1 premutation). In this renewal application, we build on the most compelling findings from the initial project period in three important ways. First, we make use of two extremely rich existing phenotypic datasets from women with the FMR1 premutation and their children with FXS, and parallel data collected from ASD families. This includes extensive longitudinal data on children with FXS. The use of these data will allow us to identify behavioral phenotypes that may constitute ASD-related signatures of the FMR1 premutation. Second, we will identify the ASD-related neural phenotypic signature in carriers of the FMR1 PM by applying new measures assessing neural response to sound-evoked brain activity. Third, we will examine molecular genetic correlates of the behavioral and neural phenotypes, along with continued banking of DNA for future studies of genotyping and data sharing. Together, this project aims to identify key behavioral, neural, and molecular-genetic markers of ASD-related endophenotypes, and therefore helps to illuminate the pathogenesis of ASD and its link to the FMR1 gene.