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Type: Journal article
Title: Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
Author: 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.
Carroll, R.
et al.
Citation: Nature Communications, 2020; 11(1):4932-1-4932-13
Publisher: Springer Nature
Issue Date: 2020
ISSN: 2041-1723
Statement of
Tianyun Wang … Luis A. Perez-Jurado … Chris Barnett, Elizabeth Thompson, Maree Shaw, Renee Carroll, Kathryn Friend, Rachel Catford … Jozef Gecz ... et al.
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.
Keywords: Neurodevelopmental disorders
Rights: © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit
DOI: 10.1038/s41467-020-18723-y
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