Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.
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Simons Foundation Autism Research Initiative grants to E.E.E. (SF191889), M.W.S. (M144095 R11154) and M.W. (SF235988) supported this work. Additional support was provided by the Howard Hughes Medical Institute (International Student Research Fellowship to S.J.S.) and the Canadian Institutes of Health Research (Doctoral Foreign Study Award to A.J.W.). E.E.E. is an Investigator of the Howard Hughes Medical Institute. We thank all the families at the participating SSC sites, as well as the principal investigators (A. L. Beaudet, R. Bernier, J. Constantino, E. H. Cook Jr, E. Fombonne, D. Geschwind, D. E. Grice, A. Klin, D. H. Ledbetter, C. Lord, C. L. Martin, D. M. Martin, R. Maxim, J. Miles, O. Ousley, B. Peterson, J. Piggot, C. Saulnier, M. W. State, W. Stone, J. S. Sutcliffe, C. A. Walsh and E. Wijsman) and the coordinators and staff at the SSC sites for the recruitment and comprehensive assessment of simplex families; the SFARI staff for facilitating access to the SSC; and the Rutgers University Cell and DNA Repository (RUCDR) for accessing biomaterials. We would also like to thank the CSHL Woodbury Sequencing Center, the Genome Institute at the Washington University School of Medicine, and Yale Center for Genomic Analysis (in particular J. Overton) for generating sequencing data; E. Antoniou and E. Ghiban for their assistance in data production at CSHL; and T. Brooks-Boone, N. Wright-Davis and M. Wojciechowski for their help in administering the project at Yale. The NHLBI GO Exome Sequencing Project and its ongoing studies produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010).
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About this article
Nature Reviews Genetics (2019)