They also point to a more complex relationship of IQ and large de novo events than has often been supposed: for example, the relatively high rates of 16p11.2 and 7q11.23 CNVs and low rates of 15q11.2-13.1 duplications seen in this study compared to others may reflect the presence of particular subpopulations of rare risk CNVs that are, in fact,

more readily ascertained in cohorts with higher BGB324 clinical trial mean IQ. The results further show that the risk associated with large de novo events is related to their greater genic content, even after controlling for larger size. This observation is consistent with two countervailing hypotheses: first, that the greater gene number is a surrogate for the increased chance of disrupting one particular gene or regulatory region because of the involvement of a www.selleckchem.com/products/Everolimus(RAD001).html larger segment of the genome; or second, that it is the contribution of multiple genes and/or

regulatory regions simultaneously within these CNVs that increases risk. Our data do not allow us to resolve this issue. 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 an association of specific de novo events. However, it is important to note that despite having higher resolution than some prior studies, we still have a clear ascertainment bias for larger CNVs. It is likely that a 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 for both sequence and structural variation. Our findings with regard to recurrent de novo events in the SSC sample identify six putative ASD loci and two of these, 7q11.23 and 16p11.2, show clear evidence for genome-wide association. Moreover, our simulation analysis suggests that the most likely outcome of the ongoing phase 2 SSC study

will be the confirmation of two to three of the remaining four intervals, namely 1q21.1, 15q13.2-13.3, 16p13.2, and 16q23.3 (CDH13). The association the of recurrent duplications at 7q11.23 points to particularly promising opportunities to illuminate the molecular mechanisms of social development. Duplications in this interval have previously been described in developmental disorders, including ASD (Berg et al., 2007 and Van der Aa et al., 2009), though these have been restricted to case reports or series, with the attendant difficulties in controlling for ascertainment bias. The identification of clear association of duplications in this controlled study of ASD is striking, given that the reciprocal deletion results in a developmental syndrome characterized in part by an empathic, gregarious, and highly social personality (Pober, 2010).