Fragile X syndrome (FXS) is associated with an increased risk of autism, with prevalence rates ranging from 25-50%. This translates to an approximate relative risk of over 100, indicating that FMR1 (the gene causing FXS) confers considerable vulnerability to autism. While efforts to uncover the causal mechanisms in autism are often confounded by multiple unknown etiologies, genetically defined syndromes such as FXS provide the rare opportunity to examine gene-brain-behavior associations in an etiologically homogeneous condition.

This project is an attempt to inform the role of FMR1 in autism symptomatology through the study of 1st degree relatives who are at increased genetic liability—relatives of individuals with autism and relatives of individuals with FXS, who are carriers of the FMR1 premutation. This project builds on our prior studies of autism and the broad autism phenotype (BAP), to examine key developmental, clinical, language, and social cognitive phenotypes shown to cosegregate with autism and the BAP. We examine these phenotypes among FXS carriers in comparison to data collected from 1st degree relatives of individuals with autism, to identify potentially overlapping profiles across groups, which may be linked to FMR1. These analyses capitalize on an unprecedented opportunity— the availability of archival childhood language and cognitive testing records from a large cohort of families of individuals with FXS and autism. Using these highly valuable data, we characterize longitudinally the language and cognitive development of autism and FXS relatives over the early school-age years and examine downstream outcomes across clinical, language, and social cognitive domains. Phenotypes are examined in relation to FMR1 variation and expression of FMRP, the fragile X-mental retardation protein that is deficient in FXS and is believed to cause the cognitive and behavioral impairments in FXS. The project helps to refine understanding of the role of FMR1 in autism symptomatology and further characterize the phenotype of the fragile X premutation.