ABSTRACT Most genetic studies consider autism spectrum disorder (ASD) and developmental disorder (DD) separately despite overwhelming comorbidity and shared genetic etiology. Here we analyzed de novo mutations (DNMs) from 15,560 ASD (6,557 are new) and 31,052 DD trios independently and combined as broader neurodevelopmental disorders (NDD) using three models. We identify 615 candidate genes (FDR 5%, 189 potentially novel) by one or more models, including 138 reaching exome-wide significance (p &lt; 3.64e-07) in all models. We find no evidence for ASD-specific genes in contrast to 18 genes significantly enriched for DD. There are 53 genes show particular mutational-bias including enrichments for missense (n=41) or truncating DNM (n=12). We find 22 genes with evidence of sex-bias including five X chromosome genes also with significant female burden ( DDX3X, MECP2, SMC1A, WDR45 , and HDAC8) . NDD risk genes group into five functional networks associating with different brain developmental lineages based on single-cell nuclei transcriptomic data, which provides important insights into disease subtypes and future functional studies.

Integrated gene analyses ofde novomutations from 46,612 trios with autism and developmental disorders