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.

Takotsubo syndrome: between evidence, myths, and misunderstandings

“…The anecdotally described concurrent onset of TS in close relatives illustrates that there must be some biological background that in conjunction with an external trigger finally results in development of TS. Genetic studies have already identified promising loci, copy number variations, and polymorphisms in TS patients [33][34][35][36][37][38][39]; however, these results require further confirmation and exploration before allowing for mechanistic conclusions. Another key toward understanding the pathogenesis of TS might be hidden in the striking gender preponderance: 90% of patients are women, and of those 80% are postmenopausal.…”

Genetic and Epigenetic Factors of Takotsubo Syndrome: A Systematic Review

“…Current research has investigated possible associations between TTS and single nucleotide polymorphisms (SNPs) in genes involved with sympathetic stress. Various studies have been published describing SNPs potentially implicated in the pathogenesis of TTS ( Table 2 ) [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ].…”

“…Current research has investigated possible associations between TTS and single nucleotide polymorphisms (SNPs) in genes involved with sympathetic stress. Various studies have been published describing SNPs potentially implicated in the pathogenesis of TTS (Table 2) [31][32][33][34][35][36][37][38][39][40][41][42][43]. The prevalence of polymorphisms of ADRB1, ADRB2, and GNAS were similar between patients and controls.…”

Genetic and Epigenetic Factors of Takotsubo Syndrome: a Systematic Review

“…Current literature has focused on the possible existence of associations between TTS and single nucleotide polymorphisms (SNPs) in genes associated with sympathetic stress. Several studies analysing polymorphisms potentially involved in the pathogenesis of TTS have been published (Table 2) [21][22][23][24][25][26][27][28][29][30][31][32][33].…”

“…The exome sequencing may be used for identifying causal variants of rare disorders by using the Next Generation Sequencing (NGS) technology. Exome analysis, genotyping array analysis, and array comparative genomic hybridization were carried out on 28 Christchurch EqSCM cases [33].…”