The Simons Foundation Autism Research Initiative (SFARI) is pleased to announce that it has awarded five grants in response to the Functional Screen of Autism-Associated Variants request for applications (RFA).

These grants will support the development and application of medium- and high-throughput screens to test the potential role of missense variants (i.e., mutations in which a single nucleotide change results in a codon that specifies a different amino acid) in conferring autism risk. Although de novo missense variants constitute the largest class of variants identified in the Simons Simplex Collection (SSC) to date, the majority of attention has been focused on de novo mutations that clearly disrupt protein function: nonsense, splice-site, and frameshift mutations.  Identification of missense variants that are pathogenic will help to support a case for particular genes in autism susceptibility.

“These successful applications outline approaches to understanding the functional effects of missense mutations that are not only creative, but also quite complementary to each other,” says SFARI Senior Scientist Alan Packer. “As such, we’re hopeful that the combined results will shed light on an important but understudied component of the genetic basis of autism.”

SFARI will provide more than $1.8 million in funding over the next 18 months as part of this award program. Contingent upon the success of this initial stage, a subset of the awarded projects will be funded for an additional 18 months (i.e., three years in total) to allow the expansion of the functional screens to a larger number of variants.

The five awardees are listed below:

• George Church, Ph.D. (Harvard Medical School)
  Human gene editing and in situ sequencing of neuronal microcircuit arrays

 

• Kurt Haas, Ph.D. (University of British Columbia)
  A multi-platform approach to the functional assessment of autism gene variants

 

• Paul Sternberg, Ph.D. (California Institute of Technology)
  Analysis of autism-associated alleles in C. elegans

 

• Michael Wangler, M.D., Shinya Yamamoto D.V.M., Ph.D. (Baylor College of Medicine)
  In vivo functional analysis of autism candidate genes

 

• Haiyuan Yu, Ph.D. (Cornell University), Bernie Devlin, Ph.D. (University of Pittsburgh), Kathryn Roeder, Ph.D. (Carnegie Mellon University)
  Interactome perturbation by large-scale mutagenesis to find autism risk variants

The SFARI blog post “Making sense out of missense mutations” discusses these projects further and highlights recent papers that have found functional evidence for missense variants contributing to autism and other disorders.