Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes

Nat Genet. 2022 Sep;54(9):1305-1319. doi: 10.1038/s41588-022-01148-2. Epub 2022 Aug 18.


To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance (P < 2.5 × 10-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1 and HNRNPUL2). The association of NAV3 with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect. Autistic individuals with LoF variants in the four moderate-risk genes (NAV3, ITSN1, SCAF1 and HNRNPUL2; n = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes (CHD8, SCN2A, ADNP, FOXP1 and SHANK3) (59% vs 88%, P = 1.9 × 10-6). Power calculations suggest that much larger numbers of autism cases are needed to identify additional moderate-risk genes.

Publication types

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

MeSH terms

  • Autism Spectrum Disorder* / genetics
  • Autistic Disorder* / genetics
  • Exome / genetics
  • Exome Sequencing
  • Forkhead Transcription Factors / genetics
  • Genetic Predisposition to Disease
  • Humans
  • Mutation
  • Repressor Proteins / genetics


  • FOXP1 protein, human
  • Forkhead Transcription Factors
  • Repressor Proteins