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 by 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.

Abbreviations: CADD, Combined Annotation Dependent DepletionFPKM, fragments per kilobase pair of exon per million fragments mappedNHLBI GO ESP, National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing ProjectPCR, polymerase chain reactionSIC, stress-induced cardiomyopathy.

Figure 1

Proposed clinical paradigm for risk stratification and treatment of patients based on knowledge of genomic status of cardiomyopathy genes. Used with permission from {Blinded}.

Figure 2

Mean variants per stress-induced cardiomyopathy (SIC) patients and controls (CONT) after exome sequencing and application of the variant filtering approach. Variants identified using the research filters were significantly greater in the SIC patients (p = 0.01, Z-score = −2.574) by the Mann-Whitney U-Test. Used with permission from {Blinded}.