De novo mutations in autism spectrum disorders revealed by whole genome sequencing. Y. H. Jiang1, R. Yuen2, X. Jin3,4, M. Wang4, N. Chen4, X. Wu4, J. Ju4, J. Mei4, Y. Shi4, L. Zwaigenbaum8, M. T. Carter5, C. Chrysler6, L. Drmic6, L. Lau2, D. Mercio2, A. Thompson6, M. Uddin2, B. Thiruvahindrapuram2, E. Anagnostou7, S. Walker2, R. Ring9, J. Wang4, C. Lajonchere9, J. Wang4,10, A. Shihi9, P. Szatmari6, H. Yang4, G. Dawson9,11, Y. Li4, S. W. Scherer2,12 1) Department of Pediatrics, Duke University School of Medicine, Durham, NC; 2) Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada; 3) BGI@CHOP, Childrens Hospital of Philadelphia, Philadelphia, PA, 19104; 4) BGI-Shenzhen, Bei Shan Road, Yantian, Shenzhen, 518083, China; 5) Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; 6) Department of Psychiatry and Behavioural Neurosciences, Offord Centre for Child Studies, McMaster University, Hamilton, Ontario L8S 4K1, Canada; 7) Bloorview Research Institute, University of Toronto, Toronto, ON M4G 1R8, Canada; 8) Department of Pediatrics, University of Alberta, Edmonton, Alberta T5G 0B7, Canada; 9) Autism Speaks, New York, NY, USA; 10) The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, and Department of Biology, University of Copenhagen, DK-2200 Copenhagen, Demark; 11) Department of Psychiatry, University of North Carolina at Chapel Hill, NC 27510, USA; 12) McLaughlin Centre, University of Toronto, Toronto, Ontario M5S 1A1, Canada.
Autism Spectrum Disorder (ASD) demonstrates high heritability and, familial clustering and ~4:1 male to female bias, yet the genetic causes are only partially understood, due to extensive clinical and genetic heterogeneity. Whole genome sequencing (WGS) promises added value to identify novel ASD risk genes as well as new mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We have initiated an international endeavor called the Autism Genome 10K-Project, which aims to sequence the genomes from 10,000 individuals belonging to Autism Speaks Autism Genetic Resource Exchange(AGRE). In a pilot study, we used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in 6 of 32 (19%) and X-linked or autosomal inherited alterations in 10 of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported, a yield that is in part due to the more comprehensive and uniform coverage afforded by WGS. Deleterious mutations variants were found in four novel, 9 known, and 8 candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1 involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (also linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough informatic analyses for de novo and rare-inherited mutations will improve the detection of genetic variants likely associated with ASD or its accompanying clinical symptoms. We have just completed WGS of second phase of 100 ASD trios. The progress of analyzing these families will also be presented.
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