Journal article
Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases
Holly AF Stessman, Bo Xiong, Bradley P Coe, Tianyun Wang, Kendra Hoekzema, Michaela Fenckova, Malin Kvarnung, Jennifer Gerdts, Sandy Trinh, Nele Cosemans, Laura Vives, Janice Lin, Tychele N Turner, Gijs Santen, Claudia Ruivenkamp, Marjolein Kriek, Arie van Haeringen, Emmelien Aten, Kathryn Friend, Jan Liebelt Show all
NATURE GENETICS | NATURE PUBLISHING GROUP | Published : 2017
DOI: 10.1038/ng.3792
Abstract
Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100). Clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic ..
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Grants
Awarded by Simons Foundation Autism Research Initiative
Awarded by NIH
Awarded by Netherlands Organization for Scientific Research
Awarded by Horizon 2020 Marie SklodowskaCurie European Training Network (MiND)
Awarded by NHGRI Interdisciplinary Training in Genome Science grant
Awarded by Australian NHMRC
Awarded by National Basic Research Program of China
Awarded by National Natural Science Foundation of China
Awarded by China Scholarship Council
Awarded by Fundamental Research Funds for the Central Universities
Awarded by National Health and Medical Research Council of Australia
Awarded by University of California, San Diego Clinical and Translational Research Institute
Awarded by National Institute of Mental Health
Awarded by EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
Awarded by NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
Awarded by NATIONAL HUMAN GENOME RESEARCH INSTITUTE
Awarded by NATIONAL INSTITUTE OF MENTAL HEALTH
Awarded by OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH
Funding Acknowledgements
We thank the individuals and their families for participation in this study. We acknowledge the Vienna Drosophila Resource Center and Bloomington Drosophila Stock Center (NIH P40OD018537). This research was supported in part by the following: the Simons Foundation Autism Research Initiative (SFARI 303241) and NIH (R01MH101221) to E.E.E.; VIDI and TOP grants (917-96-346, 912-12-109) from the Netherlands Organization for Scientific Research and Horizon 2020 Marie SklodowskaCurie European Training Network (MiND, 643051) to A.S.; an NHGRI Interdisciplinary Training in Genome Science grant (T32HG00035) to H.A.F.S. and T.N.T.; Australian NHMRC grants 1091593 and 1041920 and Channel 7 Children's Research Foundation support to J.G.; the National Basic Research Program of China (2012CB517900) and the National Natural Science Foundation of China (81330027, 81525007 and 31400919) to K.X.; the China Scholarship Council (201406370028) and the Fundamental Research Funds for the Central Universities (2012zzts110) to T.W.; National Health and Medical Research Council of Australia Project grants (556759 and 1044175) to I.E.S., P.J.L., and M.B.D., and a Practitioner Fellowship (1006110) to I.E.S.; grants from the Jack Brockhoff Foundation and Perpetual Trustees, the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS, the Swedish Brain Foundation, the Swedish Research Council, and the Stockholm County Council; the University of California, San Diego Clinical and Translational Research Institute (KL2TR00099 and 1KL2TR001444) to T.P.; and the Research FundFlanders (FWO) to R.F.K. and G.V.D.W. We are grateful to all of the families at the participating SSC sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, and E. Wijsman). We appreciate access to phenotypic data on SFARI Base. We gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families. AGRE is a program of Autism Speaks and is supported in part by grant 1U24MH081810 from the National Institute of Mental Health to C.M. Lajonchere. We thank N. Brown, K. Pereira, T. Vick, T. Desai, C. Green, A.L. Doebley, and L. Grillo for their valuable contributions as well as T. Brown for assistance in editing this manuscript. H.P. is supported as a Senior Clinical Investigator of FWO. E.E.E. is supported as an investigator of the Howard Hughes Medical Institute.