Based on consistent observations in other NDDs and our TD CNV analyses, we hypothesized that de novo LGD variants would be significantly overrepresented in TD cases versus controls. We confirmed this expectation, with de novo LGD variants showing a significantly elevated rate ratio in TD probands (rate ratio [RR] 2.14, 95% CI 1.28–3.61, p = 0.006; Figure 2A; Table 2). De novo missense (Mis) variants, particularly those predicted to be damaging by PolyPhen2 (Missense 3 or Mis3; PolyPhen2 [HDIV] score ≥ 0.957; Adzhubei et al., 2010, 2013), are also enriched in probands (RR 1.27, 95% CI 1.03–1.57, p = 0.03; Figure 2A). As a group, therefore, damaging de novo variants (Mis3 and LGD variants) occur at a significantly higher rate in coding regions in TD probands versus SSC controls (RR 1.38, 95% CI 1.14–1.67, p = 0.003). No differences were seen in the rate of de novo synonymous variants (RR 0.91, 95% CI 0.70–1.17, p = 0.8) nor in the rate of in-frame indels (RR 0.45, 95% CI 0.019–3.48, p = 0.9). A one-sided binomial exact test, which is typically
