Given the current results, a comparison to recent studies of ASD may be instructive: to date 2,517 simplex SSC ASD families have been reported, and both de novo LGD and Mis3 variants have been associated with ASD risk, with mutation rates and effect sizes consistent with those observed here (e.g., rate ratio of 2.08 versus 1.74 for de novo LGD variants in TD versus ASD) (Iossifov et al., 2014). Of note, the ascertainment strategies used in both TD cohorts did not restrict to apparently simplex families, as was done in the SSC. Given the evidence for an increased burden of de novo variation in simplex versus multiplex families in ASD (e.g., Leppa et al., 2016), it would be reasonable to hypothesize that the current analysis may underestimate the rate ratios for de novo variants in simplex TD families.
