Exome sequencing of TD trios establishes the increased rate of de novo LGD variants in cases versus controls. We observe this excess burden in two independently ascertained cohorts: TIC Genetics and TSAICG. We also observe evidence for enrichment of de novo Mis3 variants in TD probands, though statistical significance is not reached in all tests. Sequencing of additional trios is certain to clarify this result. As has been well established in exome studies of other NDDs, these results provide a highly reliable avenue for gene discovery based on the recurrence of damaging de novo mutations. In the current dataset, one gene, WWC1, meets the threshold for high-confidence association and three genes meet the threshold for probable association.
