Exome Sequencing in 8,737 Families Affected By Autism Spectrum Disorder

Oral Presentation
Thursday, May 2, 2019: 1:54 PM
Room: 516ABC (Palais des congres de Montreal)
P. Feliciano1, X. Zhou2, I. Astrovskaya1, T. Turner3, S. Xu1, J. Hall1, T. Wang4, L. Brueggeman5, L. Green Snyder1, T. Yu6, E. E. Eichler4, B. J. O'Roak7, J. J. Michaelson5, L. Grosvenor1, N. Volfovsky1, Y. Shen8, W. K. Chung9 and S. Consortium1, (1)Simons Foundation, New York, NY, (2)Department of Systems Biology, Columbia University, New York, NY, (3)University of Washington, Seattle, WA, (4)Department of Genome Science, University of Washington, Seattle, WA, (5)Psychiatry, University of Iowa, Iowa City, IA, (6)Harvard Medical School, Boston, MA, (7)Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, (8)Columbia University, New York, NY, (9)Pediatrics, Columbia University, New York, NY

Autism spectrum disorder (ASD) is a genetically heterogeneous condition, caused by a combination of rare de novo and inherited variants as well as common variants in at least several hundred genes. Previous research has identified approximately 100 high-confidence autism risk genes. However, significantly larger sample sizes are needed to identify the complete set of genetic risk factors, which are estimated to include several hundred genes. We have recruited more than 50,000 individuals with ASD and their available first-degree family members into a recontactable research cohort called SPARK (SPARKForAutism.org).


To identify new high-confidence autism risk genes and identify mechanisms of biological convergence among these genes.

To return results to individual families with genetic variants in newly discovered and previously known high-confidence autism risk genes in order to accelerate clinical research targeted to specific genetic etiologies.


Participants were recruited and consented online and provided saliva. Whole exome sequencing (WES) and genotyping data were generated for a pilot study of 457 families, including 465 individuals with autism. We subsequently expanded our analyses to 8,737 families, including 9,843 individuals with autism spectrum disorder and 17,772 of their first-degree family members. We identified several classes of genetic variants across multiple modes of inheritance (de novo, mosaic, and transmitted), including rare and deleterious single-nucleotide variants, small insertion/deletion variants and large copy number variants.


In our pilot study of 457 families, we identified nine newly emerging high-confidence autism risk genes. We also identified a returnable genetic cause in 10.8% of families. In our expanded cohort, initial analyses have identified de novo and inherited variants in genes and loci that are clinically recognized causes or significant contributors to ASD in hundreds of families. The dataset has also identified numerous novel candidate loci, which are now being investigated. In order to accelerate knowledge in ASD, we have released all genomic and phenotypic data from these families to the research community.


We have developed an interdisciplinary, collaborative high-throughput workflow for identifying, confirming and returning individual genetic results related to autism spectrum disorder to hundreds of research participants. Further analyses will greatly increase the number of high-confidence genetic risk factors associated with ASD and also contribute to a deeper mechanistic understanding of the genes and pathways that lead to ASD during development. Returning genetic results to SPARK participants will enable autism research that incorporates genetic etiology at scale.

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