Rare Variants in Cardiomyopathy Genes Associated With Stress-Induced Cardiomyopathy

Abstract

Background Stress-induced cardiomyopathy (SIC) is a poorly understood condition associated with periods of emotional and physical stress. The clinical approaches for management of SIC are supportive and reactive to patient symptoms. Objective To utilize next-generation exome sequencing to define genetic variation associated with, and potentially responsible for, this disease. Methods We performed exome sequencing of 7 white female patients with SIC. Filtering of the identified variants was performed to limit our investigation to those sequences that passed quality control criteria, were rare or novel, were determined algorithmically to have high impact on the associated protein, and were within regions of high species conservation. All variants were verified using Sanger sequencing. Results Exome-sequencing analysis revealed that each patient carried predicted deleterious variants affecting known cardiomyopathy genes. In each case, the identified variant was either not previously found in public human genome data or was previously annotated in a database of clinical variants associated with cardiac dysfunction. Conclusion Patients with SIC harbor deleterious mutations in established cardiomyopathy genes at a level higher than healthy controls. We hypothesize that patients at highest risk for SIC likely live in a compensated state of cardiac dysfunction that manifests clinically only after the myocardium is stressed. In short, we propose that SIC is another example of an occult cardiomyopathy with a distinct physiological trigger and suggest that alternative clinical approaches to these patients may be warranted.

Takotsubo cardiomyopathy and Brugada syndrome in a patient with a novel loss-of-function variant in the cardiac sodium channel Nav1.5

“…The specific variant we identified in SCN5A, R376L, has not been described in the literature, but the SCN5A H558R variant has been associated with TTC in a genome-wide association study, suggesting a possible association. 4 However, the coexistence of TTC and the genetic variant in the SCN5A gene likely is coincidental, and we have no data supporting an association between the variant, BrS, and occurrence of TTC. This highlights the uncertainty that follows the interpretation of genetic findings, which should be made clear to the patient by the physician before performing genetic testing.…”

“…3 The first genome-wide association study (GWAS) conducted on a cohort of 96 patients with TTC found some potential genetic risk variants but the study was too small to be conclusive. 11 Variants in genes associated with various cardiomyopathies have been identified in patients with TTC, 4 but genetic variants associated with electrical disturbances have also been described. A case report described TTC in a patient with long QT syndrome (LQTS) and a genetic variant in the KCNH2 gene.…”

“… 3 Rare, genetic variants have been found in patients with TTC, including variants in the SCN5A gene encoding the Na v 1.5 sodium channel. 4 Variants in the SCN5A gene are also associated with Brugada syndrome (BrS), a genetic disorder with a characteristic repolarization pattern on the ECG leading to increased risk of ventricular arrhythmias. 5 Previously, case reports have described TTC in patients with a Brugada pattern on the ECG (Brugada phenocopy).…”

Genetic and Epigenetic Factors of Takotsubo Syndrome: A Systematic Review

“…In 2016, an exome sequencing study was performed on seven female sporadic TTS patients [ 48 ], evidencing in all subjects predicted deleterious variants in described cardiomyopathy genes. The variants were not described in public human genome data or in a public database associated with cardiac dysfunction.…”

Genetic and Epigenetic Factors of Takotsubo Syndrome: a Systematic Review

“…In 2016, Kalani group performed exome sequencing of 7 female sporadic patients with TTS [38]. Exome-sequencing analysis revealed that each patient carried predicted deleterious variants affecting known cardiomyopathy genes.…”