Figure 2. De Novo Variants Are Associated with Risk in the TIC Genetics Cohort.
We first compared the rate of de novo mutation per base pair(bp) in the TIC Genetics and SSC cohorts. We determined the “total callable exome” for each TD proband or SSC sibling (Table 1; Table S1). We then calculated the mutation rate per bp for each individual based on the observed number of de novo variants and the size of the callable exome. The mean of these rates is plotted by cohort in (A) and (B) (see left y axis; see also Table 2). To estimate rate ratios and p values, we compared the number of mutations observed per the number of callable bp assessed using a one-sided rate ratio test. We estimated the theoretical rate of coding de novo variants per individual by multiplying the variant rate by the size of the “coding” exome (RefSeq hg19 coding exons; 33,828,798 bp). We display this as the right y axis in (A) and (B). We compare the main classes of variants in (A). All classes of de novo non-synonymous variants show a significantly elevated rate ratio in TD probands (red) versus SSC siblings (blue). As expected, de novo synonymous variants are not significantly overrepresented in TD probands (p = 0.8). We compare subclasses of LGD variants in (B). Frameshift (FS) indels trend toward a higher rate ratio (RR) than LGD SNVs (RR 6.0, p = 0.003 versus RR 1.5,p = 0.1). In-frame indels, which are not expected to have marked biological impact, are not significantly overrepresented in TD probands (p = 0.9).Aone- sided binomial exact test to assess the significance of the observed burden differences in TD cases versus controls produced consistent results (Figure S2). Mis3, missense variants predicted to be damaging by PolyPhen (Missense 3 or Mis3; PolyPhen2 [HDIV] score ≥ 0.957).