This study investigates the role of de novo mutations in autism spectrum disorders (ASDs) by sequencing the exomes of 175 ASD trios. The results show that only 46.3% of cases carry a missense or nonsense de novo variant, and the overall mutation rate is only slightly higher than expected. However, there is significant enrichment in protein connectivity among genes harboring de novo missense or nonsense mutations, and these proteins are also connected to previously identified ASD genes. The study suggests that a subset of observed de novo events are relevant to ASD risk, but the majority of these events are unconnected to ASD. Genetic models indicate that the risk conferred by de novo events is distributed across many genes and is incompletely penetrant. The study also highlights CHD8 and KATNAL2 as genuine autism risk factors. Despite the substantial heritability of ASD, few genetic risk factors have been identified, and the findings support polygenic models where spontaneous coding mutations in a large number of genes increase risk by 5 to 20-fold.This study investigates the role of de novo mutations in autism spectrum disorders (ASDs) by sequencing the exomes of 175 ASD trios. The results show that only 46.3% of cases carry a missense or nonsense de novo variant, and the overall mutation rate is only slightly higher than expected. However, there is significant enrichment in protein connectivity among genes harboring de novo missense or nonsense mutations, and these proteins are also connected to previously identified ASD genes. The study suggests that a subset of observed de novo events are relevant to ASD risk, but the majority of these events are unconnected to ASD. Genetic models indicate that the risk conferred by de novo events is distributed across many genes and is incompletely penetrant. The study also highlights CHD8 and KATNAL2 as genuine autism risk factors. Despite the substantial heritability of ASD, few genetic risk factors have been identified, and the findings support polygenic models where spontaneous coding mutations in a large number of genes increase risk by 5 to 20-fold.