Functional Screen of Autism-Associated Variants Request for Applications

Grants awarded through this request for applications (RFA) were intended to advance our understanding of the genetic basis of autism, and in particular the potential role of missense and in-frame deletion variants in conferring risk.

Data to be analyzed under this RFA came in part from the exome sequencing of more than 2,500 families from the Simons Simplex Collection (SSC). Although much attention has been focused on de novo mutations that clearly disable protein function — nonsense, splice-site, and frameshift mutations — the majority of what has been identified in the SSC falls into the category of missense variants of uncertain significance. The sequencing of additional large cohorts may help to distinguish pathogenic from benign variants on a purely statistical basis, but it is clear that these efforts will have to be complemented by screens to test such variants for functional relevance.

To this end, we sought proposals for the development and application of medium- or high-throughput screens to test for the functional effects of missense and in-frame deletion variants identified in the SSC and other autism collections. In addition to establishing the functional impact of de novo missense mutations, one key goal was to compare the impact of such variants when inherited in individuals with autism vs. unaffected siblings (or those with autism vs. unrelated controls), to support a case for particular genes in autism susceptibility.