Excess of RALGAPB de novo variants in neurodevelopmental disorders

Eur J Med Genet. 2020 Nov;63(11):104041. doi: 10.1016/j.ejmg.2020.104041. Epub 2020 Aug 24.


Autism spectrum disorder is a neurodevelopmental disorder (NDD) with complex genetic architecture marked primarily by social and communication impairments along with deficits in restrictive and repetitive behaviors. Due to the complex nature and genetic heterogeneity of the disease, genotype and phenotype correlation remains challenging. Prior studies have implicated RALGAPB as a candidate gene for ASD, but stringent analysis is required to determine the pathogenicity. By targeted sequencing, we identified a new de novo RALGAPB missense variant (c.1238C> T; p.T413M) in an ASD family. By leveraging published large-scale genome sequencing studies, we curated five de novo likely gene-disruptive (LGD) variants and 5 de novo missense variants in ASD and related NDDs and revealed a genome-wide significant excess of RALGAPB de novo LGD variants (P_adjust = 0.0053). Quantitative reverse transcription PCR revealed that the frameshift variant c.1927dupA; p.N643fs*3 reduced mRNA expression levels confirming the loss-of-function effect. Co-expression analysis using human brain transcriptome data provide the potential functional link of RALGAPB and 38 ASD and/or NDD genes. Our study suggests RALGAPB as a new NDD risk gene which should be considered in clinical diagnosis of ASD and related NDDs.

Keywords: Autism spectrum disorder; Epilepsy; Neurodevelopmental disorder; RALGAPB; de novo variants.

Publication types

  • Case Reports

MeSH terms

  • Autism Spectrum Disorder / genetics*
  • Autism Spectrum Disorder / pathology
  • Cells, Cultured
  • Child
  • Computational Biology
  • Frameshift Mutation
  • GTPase-Activating Proteins / genetics*
  • GTPase-Activating Proteins / metabolism
  • Humans
  • Male
  • Pedigree
  • Prefrontal Cortex / embryology
  • Prefrontal Cortex / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism


  • GTPase-Activating Proteins
  • RALGAPB protein, human
  • RNA, Messenger