The nature of rare CNV alleles in psychiatric disease -risk alleles arising by recent de novo mutation, conferring significant disease risks, and having highly variable phenotypic expression - is likely to be the nature of rare alleles in general. This knowledge will serve as a guide as we move forward into the era of complete genome sequencing. Genetic approaches that have worked well for CNVs (Figure 3) should adapt well to sequencing platforms. Indeed the pioneering exome studies of ASD and schizophrenia have begun with a strong focus on de novo mutations in trios, with compelling preliminary results (Girard et al., 2011; O’Roak et al., 2011; Vissers et al., 2010; Xu et al., 2011). As always, success will depend on statistical power and sample size. However, as we move ahead, success will increasingly depend on our ability to integrate the signal from de novo, inherited, common, and rare forms of variation in the genome.
