The pathophysiology of stress cardiomyopathy (SCM), also known as takotsubo syndrome, is poorly understood. SCM usually occurs sporadically, often in association with a stressful event, but clusters of cases are reported after major natural disasters. There is some evidence that this is a familial condition. We have examined three possible models for an underlying genetic predisposition to SCM. Our primary study cohort consists of 28 women who suffered SCM as a result of two devastating earthquakes that struck the city of Christchurch, New Zealand, in 2010 and 2011. To seek possible underlying genetic factors we carried out exome analysis, Cardio-MetaboChip genotyping array analysis and array comparative genomic hybridization on these subjects. The most striking finding from these analyses was the observation of a markedly elevated rate of rare, heterogeneous copy number variants (CNV) of uncertain clinical significance (in 12/28 subjects). Several of these CNVs clearly impacted on genes of cardiac relevance including RBFOX1, GPC5, KCNRG, CHODL , and GPBP1L1 . There is no physical overlap between the CNVs, and the genes they impact do not fall into a clear pathophysiological pathway. However, the recognition that SCM cases display a high rate of unusual CNV, and that SCM predisposition may therefore be associated with these CNVs, offers a novel perspective and a new approach by which to understand this enigmatic condition.