Targeted massively parallel sequencing of autism spectrum disorder-associated genes in a case control cohort reveals rare loss-of-function risk variants.

Authors:
Anthony J Griswold
Anthony J Griswold
University of Miami
United States
Nicole D Dueker
Nicole D Dueker
John P. Hussman Institute for Human Genomics
Joseph A Rantus
Joseph A Rantus
University of Miami
James M Jaworski
James M Jaworski
John P. Hussman Institute for Human Genomics
Susan H Slifer
Susan H Slifer
Duke University Medical Center
United States
Michael A Schmidt
Michael A Schmidt
Massachusetts Institute of Technology
United States
William Hulme
William Hulme
University of Miami Miller School of Medicine
United States

Mol Autism 2015 7;6:43. Epub 2015 Jul 7.

John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136 USA ; Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL 33136 USA.

Background: Autism spectrum disorder (ASD) is highly heritable, yet genome-wide association studies (GWAS), copy number variation screens, and candidate gene association studies have found no single factor accounting for a large percentage of genetic risk. ASD trio exome sequencing studies have revealed genes with recurrent de novo loss-of-function variants as strong risk factors, but there are relatively few recurrently affected genes while as many as 1000 genes are predicted to play a role. As such, it is critical to identify the remaining rare and low-frequency variants contributing to ASD.

Methods: We have utilized an approach of prioritization of genes by GWAS and follow-up with massively parallel sequencing in a case-control cohort. Using a previously reported ASD noise reduction GWAS analyses, we prioritized 837 RefSeq genes for custom targeting and sequencing. We sequenced the coding regions of those genes in 2071 ASD cases and 904 controls of European white ancestry. We applied comprehensive annotation to identify single variants which could confer ASD risk and also gene-based association analysis to identify sets of rare variants associated with ASD.

Results: We identified a significant over-representation of rare loss-of-function variants in genes previously associated with ASD, including a de novo premature stop variant in the well-established ASD candidate gene RBFOX1. Furthermore, ASD cases were more likely to have two damaging missense variants in candidate genes than controls. Finally, gene-based rare variant association implicates genes functioning in excitatory neurotransmission and neurite outgrowth and guidance pathways including CACNAD2, KCNH7, and NRXN1.

Conclusions: We find suggestive evidence that rare variants in synaptic genes are associated with ASD and that loss-of-function mutations in ASD candidate genes are a major risk factor, and we implicate damaging mutations in glutamate signaling receptors and neuronal adhesion and guidance molecules. Furthermore, the role of de novo mutations in ASD remains to be fully investigated as we identified the first reported protein-truncating variant in RBFOX1 in ASD. Overall, this work, combined with others in the field, suggests a convergence of genes and molecular pathways underlying ASD etiology.

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http://dx.doi.org/10.1186/s13229-015-0034-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504419PMC
July 2015
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