The identification of novel autism pathogenicity genes and their associated phenotypes. H. A. F. Stessman1, B. J. O'Roak2, E. A. Boyle1, K. T. Witherspoon1, B. Martin1, C. Lee1, L. Vives1, C. Baker1, J. Hiatt1, D. A. Nickerson1, R. Bernier3, J. Shendure1, E. E. Eichler1,4 1) Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA; 2) Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR; 3) Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA; 4) Howard Hughes Medical Institute, Seattle, WA.

   Exome sequencing of families with cases of sporadic autism spectrum disorder (ASD) has suggested remarkable genetic heterogeneity with the identification of hundreds of candidate genes (>500) carrying sporadic disruptive mutations. Using modified molecular inversion probes (MIPs) and an established statistical framework for evaluating the likelihood of recurrent mutations at individual genes (ORoak et al., Science, 2012), we applied a genotype-first approach to identify loci with an excess of de novo mutation (Stessman et al., Cell, 2014). We have now applied this approach to 99 candidate genes selected for their severity, recurrence, and strong biological network association. We increased overall capture efficiency as well as our ability to identify germline mosaicism by implementing small single-molecule tags into our MIP design (Hiatt et al., Genome Research, 2013). In our most recent screen of 64 genes, over 3,700 probands and >2,500 unaffected siblings were scored for de novo mutations with >95% of the target regions uniquely captured 10 or more times. We have now identified 10 loci that show an excess (p < 0.05) of de novo mutation in ASD probandsCHD8, PTEN, TBR1, GRIN2B, DYRK1A, ADNP, CHD2, SYNGAP1, TRIP12, and PAX5which may contribute to 1.5% of sporadic ASD. In addition, there are many genes where at least two recurrent de novo mutations have now been identified that have not yet reached significance, including CTNNB1, SLC6A1, PPP2R5D, TCF7L2, and DSCAM. Importantly, the total burden of de novo mutations was highly significant and skewed toward more severe events for probands in contrast to unaffected siblings. Recontact of patients with CHD8, DYRK1A, and ADNP de novo mutations has identified subtle phenotypic differences that suggest specific ASD subtypes associated with macrocephaly, intellectual disability, gastrointestinal dysfunction, epilepsy, and/or sleep dysfunction. This study reinforces the importance of de novo mutations in ASD and further highlights the strength of our genotype-first approach to identify new genetic subtypes of a highly heterogeneous disease.

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