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

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.; Liebelt, J.; Barnett, C.; Haan, E.; Shaw, M.; Gecz, J.; Anderlid, B. -M.; Nordgren, A.; Lindstrand, A.; Schwartz, C.; Kooy, R. F.; Vandeweyer, G.; Helsmoortel, C.; Romano, C.; Alberti, A.; Vinci, M.; Avola, E.; Giusto, S.; Courchesne, E.; Pramparo, T.; Pierce, K.; Nalabolu, S.; Amaral, D. G.; Scheffer, I. E.; Delatycki, M. B.; Lockhart, P. J.; Hormozdiari, F.; Harich, B.; Castells-Nobau, A.; Xia, K.; Peeters, H.; Nordenskjold, M.; Schenck, A.; Bernier, R. A.; Eichler, E. E.

doi:10.1038/ng.3792

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.