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

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 x10(-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 x10(-6)). Power calculations suggest that much larger numbers of autism cases are needed to identify additional moderate-risk genes.

Automated summary

In a comprehensive analysis of autism cases, we identified 60 genes, including five new risk genes, that are significantly associated with autism risk. The NAV3 gene is primarily associated with autism risk through rare inherited variants and has a moderate effect. Autistic individuals with moderate-risk genes show less cognitive impairment compared to those with highly penetrant genes.