Association with disease is more difficult to establish for very rare genetic variants. In this study, we pooled deletions and duplications, considering them together. This approach allowed us to present statistical evidence for the connection of ZNF804A CNVs to psychiatric disorders. In addition, the large-scale nature of the structural alterations reported here makes phenotypic effects more likely, compared with most sequence changes. Both the deletions identified here remove the entire sequence of ZNF804A (Figure 1), which is likely to result in differences in mRNA abundance that may have downstream consequences, especially because ZNF804A is a putative transcription factor, a class of protein that has often been implicated in haploinsufficiency disorders.44 The duplication that includes one or two exons of ZNF804A (Figure 1) may lead to a protein that acts in a dominant-negative manner, interfering with the actions of the wild-type ZNF804A, or, because of the manner in which the duplicated sequence is inserted, the event may result in alterations in the transcription of the original copy of ZNF804A.
