Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but are not yet significant for case–control mutation burden analysis. Here, we sequenced 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. Combined with published data, we assessed a total of 125 genes in over 16,000 NDD cases and compared the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach exome-wide significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluated DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes are enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); 61 reach exome-wide significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype–genotype correlations for seven NDD risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.