The presence of multiple regions showing overlapping rare de novo CNVs restricted to probands, and the absence of similar findings in their sibling controls, is striking. However, in contrast to genome-wide common variant association studies, there is no widely accepted statistical approach or threshold to formally evaluate these results. Consequently, we set out to develop a rigorous method to assess the genome-wide significance of de novo events (methods). To do so, we determined the null expectation for recurrent rare de novo CNVs based on our data from unaffected siblings and then used this expectation to evaluate the p-value for finding multiple recurrences in probands.
