Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

The SPARK Consortium

Research output: Contribution to journalArticlepeer-review

103 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

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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