Having observed that putatively deleterious de novo variants are overrepresented in both TIC Genetics and TSAICG probands separately, and that the overall rate of de novo mutations was not significantly different by cohort (Figure S5), we combined the TIC Genetics and TSAICG cohorts (484 TD trios) to obtain an overall estimate for de novo variant burden in TD (Figure 4). We observed a significant excess of de novo LGD variants (RR 2.32, 95% CI 1.37–3.93, p = 0.002, Poisson regression) and de novo damaging (LGD + Mis3) variants (RR 1.37, 95% CI 1.11–1.69, p = 0.003). Mis3 variants alone again showed a trend toward enrichment in the combined data (RR 1.24, 95% CI 0.98–1.55, p = 0.07). We observed similar results with the binomial exact and rate ratio tests (Figures 3A and 3B; Table 2; Table S2), as well as a Fisher exact test normalizing for the rate of de novo synonymous variants (Figure S6).
