The level of sequence variation identified in our study is unlikely to be exceptional, and indeed is consistent with evidence emerging from other genome sequencing studies.74 Consequently, it will be challenging to demonstrate robust (replicated) association by statistical evidence alone in case–control studies, exceptionally so with the numbers of patients that are currently affordable for sequencing. The original t(1;11) family illustrates the added issue of variable penetrance and cross-boundary diagnosis for a given mutation: ∼70% of carriers had SZ, BP or rMDD, but ∼30% had no formal psychiatric diagnosis, yet t(1;11) carriers, including both affected and unaffected, had ERP P300 measures in the range typical of individuals with SZ.5 The original identification of 37W in a case of SZ and here in a case of rMDD (and two offspring, one with rMDD, the other generalised anxiety disorder) may suggest variable penetrance of this biologically functional variant.44 Of note, the 37W variant was not observed in 10 000 control individuals,11 the 1000 Genomes project,61 the NHLBI GO Exome Sequencing Project (ESP), nor any of our 889 control samples. These findings on
