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

22 Despite the known heritable nature of autism spectrum disorder (ASD), studies have primarily 23 identified risk genes with de novo variants (DNVs). To capture the full spectrum of ASD genetic 24 risk, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 25 ASD cases, including 35,130 new cases recruited online by SPARK. In the first stage, we analyzed 26 19,843 cases with one or both biological parents and found that known ASD or 27 neurodevelopmental disorder (NDD) risk genes explain nearly 70% of the genetic burden 28 conferred by DNVs. In contrast, less than 20% of genetic risk conferred by rare inherited loss-of29 function (LoF) variants are explained by known ASD/NDD genes. We selected 404 genes based 30 on the first stage of analysis and performed a meta-analysis with an additional 22,764 cases and 31 236,000 population controls. We identified 60 genes with exome-wide significance (p < 2.5e-6), 32 including five new risk genes (NAV3, ITSN1, MARK2, SCAF1, and HNRNPUL2). The association of 33 NAV3 with ASD risk is entirely driven by rare inherited LoFs variants, with an average relative 34 risk of 4, consistent with moderate effect. ASD individuals with LoF variants in the four 35 moderate risk genes (NAV3, ITSN1, SCAF1, and HNRNPUL2, n = 95) have less cognitive 36 impairment compared to 129 ASD individuals with LoF variants in well-established, highly 37 penetrant ASD risk genes (CHD8, SCN2A, ADNP, FOXP1, SHANK3) (59% vs. 88%, p= 1.9e-06) . 38 These findings will guide future gene discovery efforts and suggest that much larger numbers of 39 ASD cases and controls are needed to identify additional genes that confer moderate risk of 40 ASD through rare, inherited variants. 41 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted October 11, 2021. ; https://doi.org/10.1101/2021.10.08.21264256 doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.