Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

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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
    Metadata
    Show full item record
    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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