Interestingly, we did not find an overall excess of rare CNVs in TS cases versus controls, as has been observed for ASD and SCZ (33, 55). However, it is also worth noting that in our analysis of more than 1000 simplex autism families, the significant increase in the burden of all rare CNVs was entirely accounted for by the contribution of a proportionally small number of large multigenic de novo events. In the present study, we observed a similar trend, with the mean size of rare de novo events in cases approximately 20x larger than those in controls and encompassing about four times as many genes. However, in the current study these differences were not statistically significant, a plausible consequence of our small sample size. A larger family cohort will be required to more definitively test the hypothesis that de novo CNVs, and particularly large multi-genic events, carry risk for TS.
