Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

The SPARK Consortium

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42 Scopus citations


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.

Original languageEnglish (US)
Article number4932
JournalNature communications
Issue number1
StatePublished - Oct 1 2020

Bibliographical note

Funding Information:
The authors are grateful to all of the families for participation in this study. We thank the following: the SPARK Consortium for access to the SPARK-27K exome data; Tychele N. Turner for the early access of autism sex-biased candidate genes during gene selection; Marlies Schimmel-Naber for help with sample management and logistics of the Rad-boudUMC cohort; Cherie Green for the help in the preparation of Melbourne samples; Yafei Mao for the helpful discussion during the manuscript preparation; and Tonia Brown for assistance in editing this manuscript. This work was supported, in part, by a US National Institutes of Health (NIH) grant (R01MH101221) and a grant from the Simons Foundation (SFARI #608045) to E.E.E.; National Natural Science Foundation of China (NSFC) (81525007 and 81730036) and the Science and Technology Projects of Hunan Province (2018SK1030) to K.X.; Australian National Health and Medical Research Council (APP1091593 and 1155224) and Channel 7 Children’s Research Foundation to J.G. The Charles University group was supported by grant 17-29423A from the Czech Ministry of Health. R.F.K. acknowledges support of the Research Fund of the University of Antwerp (Methusalem-OEC grant—GENOMED). The BOA study was partly funded by a grant assigned to N. Rommelse by the Netherlands Organization for Scientific Research (NWO grant #91610024). C.R., E.A., G.C., M.E., and D.G. were supported in part by the Italian Ministry of Health (RC2019 no. 2751604). I.E.S., M.D., and P.J.L. were supported by an Australian National Health and Medical Research Council project grant; I.E.S. is supported by a NHRMC Practitioner Fellowship and P.J.L. is supported by the Vincent Chiodo Foundation. A.S. and M.A.G. were supported by NIH Genome Training Grant T32 HG000035-23. G.V.D.W. holds an FWO postdoctoral fellowship. We thank Daniel H. Geschwind for the early access of the candidate genes from their autism network analysis, which was supported, in part, by NIH (R01MH109912). E.E.E. is an investigator of the Howard Hughes Medical Institute.

Publisher Copyright:
© 2020, The Author(s).


  • Basic Helix-Loop-Helix Transcription Factors/genetics
  • CCCTC-Binding Factor/genetics
  • Case-Control Studies
  • Cohort Studies
  • DNA Mutational Analysis
  • DNA-Binding Proteins/genetics
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Heterogeneous-Nuclear Ribonucleoprotein U/genetics
  • High-Throughput Nucleotide Sequencing
  • Humans
  • KCNQ3 Potassium Channel/genetics
  • Male
  • Mutation
  • Neurodevelopmental Disorders/genetics
  • RNA-Binding Proteins/genetics
  • Repressor Proteins/genetics
  • Transcription Factors/genetics

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Multicenter Study
  • Journal Article
  • Research Support, N.I.H., Extramural


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