Our data do not allow us to resolve this issue. Nonetheless we suspect that if many deletions or duplications encompassing small numbers of genes were as highly penetrant as multigenic events, we would have begun to show more evidence for this either in the form of an overall increased burden for smaller de novo variations and/or association of specific de novo events. However, it is important to note that despite higher resolution than some prior studies, we nonetheless have a clear ascertainment bias for detection of larger CNVs. It is likely that the combination of high-throughput sequencing, larger patient cohorts, and increasingly sophisticated approaches to evaluating combinations of risk variants will begin to shed light on this issue, with regard to both sequence and structural variation.
