Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Wang, T; Hoekzema, K; Vecchio, D; Wu, H; Sulovari, A; Coe, BP; Gillentine, MA; Wilfert, AB; Perez-Jurado, LA; Kvarnung, M; Sleyp, Y; Earl, RK; Rosenfeld, JA; Geisheker, MR; Han, L; Du, B; Barnett, C; Thompson, E; Shaw, M; Carroll, R; Friend, K; Catford, R; Palmer, EE; Zou, X; Ou, J; Li, H; Guo, H; Gerdts, J; Avola, E; Calabrese, G; Elia, M; Greco, D; Lindstrand, A; Nordgren, A; Anderlid, B-M; Vandeweyer, G; Van Dijck, A; Van der Aa, N; McKenna, B; Hancarova, M; Bendova, S; Havlovicova, M; Malerba, G; Dalla Bernardina, B; Muglia, P; van Haeringen, A; Hoffer, MJV; Franke, B; Cappuccio, G; Delatycki, M; Lockhart, PJ; Manning, MA; Liu, P; Scheffer, IE; Brunetti-Pierri, N; Rommelse, N; Amaral, DG; Santen, GWE; Trabetti, E; Sedlacek, Z; Michaelson, JJ; Pierce, K; Courchesne, E; Kooy, RF; Nordenskjold, M; Romano, C; Peeters, H; Bernier, RA; Gecz, J; Xia, K; Eichler, EE

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Author

Wang, T; Hoekzema, K; Vecchio, D; Wu, H; Sulovari, A; Coe, BP; Gillentine, MA; Wilfert, AB; Perez-Jurado, LA; Kvarnung, M; ...

Date

2020-10-01

Source Title

Nature Communications

Publisher

NATURE RESEARCH

University of Melbourne Author/s

Lockhart, Paul; Delatycki, Martin; Scheffer, Ingrid

Affiliation

Paediatrics (RCH)
Melbourne School of Population and Global Health
Medicine and Radiology

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Document Type

Journal Article

Citations

Wang, T., Hoekzema, K., Vecchio, D., Wu, H., Sulovari, A., Coe, B. P., Gillentine, M. A., Wilfert, A. B., Perez-Jurado, L. A., Kvarnung, M., Sleyp, Y., Earl, R. K., Rosenfeld, J. A., Geisheker, M. R., Han, L., Du, B., Barnett, C., Thompson, E., Shaw, M. ,... Eichler, E. E. (2020). Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders. NATURE COMMUNICATIONS, 11 (1), https://doi.org/10.1038/s41467-020-18723-y.

Access Status

Open Access

URI

http://hdl.handle.net/11343/251667

DOI

10.1038/s41467-020-18723-y

Abstract

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.

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