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

Abstract

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, genotyping array analysis, and array comparative genomic hybridization on these subjects. The most striking finding 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 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 appear to be functionally related. The recognition that SCM predisposition may be associated with a high rate of rare CNVs offers a novel perspective on this enigmatic condition.

Figure 1

CNV detected in EqSCM case 01. (A) Chromosomal location of the CNV at the RBFOX1 locus of chromosome 16. (B) Enlargement of the fifteen probe deletion (139 kb, delimited by vertical green lines and blue shading) illustrating loss of the fMet-containing exon (pale blue vertical bar) for three major RBFOX1 isoforms. DGV track of known CNVs shown at bottom of figure, beneath the genes and regions of interest tracks. Graphical views from Genoglyphix (PerkinElmer) software.

Figure 2

Genome wide distribution of CNVs. CNVs detected in 12 (of 28) EqSCM individuals by aCGH analysis. Numbers beside arrows relate to EqSCM patient number. Red arrows denote deletions, blue arrows duplications. Note that EqSCM 03, EqSCM 06, EqSCM 11 carry two rare CNVs, while EqSCM 19 contains three.