Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases

Holly A.F. 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 LiebeltChristopher Barnett, Eric Haan, Marie Shaw, Jozef Gecz, Britt Marie Anderlid, Ann Nordgren, Anna Lindstrand, Charles Schwartz, R. Frank Kooy, Geert Vandeweyer, Celine Helsmoortel, Corrado Romano, Antonino Alberti, Mirella Vinci, Emanuela Avola, Stefania Giusto, Eric Courchesne, Tiziano Pramparo, Karen Pierce, Srinivasa Nalabolu, David G. Amaral, Ingrid E. Scheffer, Martin B. Delatycki, Paul J. Lockhart, Fereydoun Hormozdiari, Benjamin Harich, Anna Castells-Nobau, Kun Xia, Hilde Peeters, Magnus Nordenskjöld, Annette Schenck, Raphael A. Bernier, Evan E. Eichler

Research output: Contribution to journalArticle

142 Scopus citations

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 forms of disease.

Original languageEnglish (US)
Pages (from-to)515-526
Number of pages12
JournalNature genetics
Volume49
Issue number4
DOIs
StatePublished - Mar 30 2017

All Science Journal Classification (ASJC) codes

  • Genetics

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    Stessman, H. A. F., Xiong, B., Coe, B. P., Wang, T., Hoekzema, K., Fenckova, M., Kvarnung, M., Gerdts, J., Trinh, S., Cosemans, N., Vives, L., Lin, J., Turner, T. N., Santen, G., Ruivenkamp, C., Kriek, M., Van Haeringen, A., Aten, E., Friend, K., ... Eichler, E. E. (2017). Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nature genetics, 49(4), 515-526. https://doi.org/10.1038/ng.3792