We next asked whether de novo variants cluster within specific genes. Here we considered only de novo damaging variants that confirmed using Sanger sequencing (Table S2). We chose to focus on de novo damaging variants because both LGD and Mis3 variants showed evidence of TD association. We identified five genes with multiple (two or more) de novo LGD or Mis3 variants. None of these had two de novo LGD variants. Based on our MLE of 420 risk genes, we estimated the per-gene p and q values for these observations with TADA, using the de novo only algorithm (He et al., 2013). Based on previously established q value thresholds (FDR thresholds) (De Rubeis et al., 2014; He et al., 2013; Sanders et al., 2015), one of these genes is a high-confidence TD (hcTD) gene (q < 0.1)— WWC1 (WW and C2 domain containing 1)—and three of these genes are probable TD (pTD) risk genes (q < 0.3)— CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), NIPBL (Nipped-B-like), and FN1 (fibronectin 1) (Figure 5B).
