the null expectation for de novo recurrence clearly detected association. It is certain that the SSC sample ascertainment process enhanced certain findings and attenuated others. There is little question that restricting the comparison group to matched siblings limited power to identify association of specific rare recurrent transmitted events; our assessment of significance for de novo CNVs was based on conservative assumptions and may have excluded true risk loci; the filtering for rare de novo CNVs and the small sample size curtailed the assessment of multi-hit hypotheses; the generally older parental age may have obscured the relationship between age and de novo variation (Figure S3) and, as noted, poor specificity at the lower bound of detection limited our assessment of small de novo structural variations.
