Copy number variants implicate cardiac function and development pathways in earthquake-induced stress cardiomyopathy

Abstract

AbstractThe 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 includingRBFOX1, GPC5, KCNRG, CHODL, andGPBP1L1. 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.