Clinical Utility of Using Next Generation Sequencing in Life Threatening Ventricular Arrhythmia

PURPOSE: Ventricular fibrillation (VF) and ventricular tachycardia (VT) are major causes of sudden cardiac death. In some cases clinical investigations fail to identify the underlying cause and the event is classified as idiopathic (iVT). Recent achievements in molecular genetics has unveiled the complex molecular basis of many cardiac conditions, paving the way for routine use of gene testing in clinical practice. In current practice, genetic testing can be used in a clinically affected patient to confirm diagnosis, or to formulate a differential diagnosis among overlapping phenotypes or between hereditary and acquired (nongenetic) forms of disease. We aimed to identify genetic variants potentially contributing to the life-threatening arrhythmias using targeted next-generation sequencing (NGS) approach in Kazakhstani patients with arrhythmias.

METHODS: The study included 92 Kazakhstani patients (mean age of 31.2 years at the time of the VT event), diagnosed with iVT, VT and coronary heart disease (CHD), VT and dilated cardiomyopathy (DCM). We developed a targeted panel of 96 known cardiac disease genes, associated with cardiomyopathy and arrhythmia.

RESULTS: We observed 168 mutations (61 distinct) listed in the Human Genome Mutation Database and another 256 rare/unique variants with elevated pathogenic potential. Also we analyzed observed mutations according to ACMG guidelines. The majority of VT/CHD patients carried known mutations and rare variants with high pathogenetic potential in the same genes and at a comparable frequency as observed for VT/DCM and iVT patients. The most abundant mutations observed for the CHD group locate to MYBPC3, DMD, LAMA2, MYH6 and GAA. A subset of patients originally diagnosed with iVT carry clinically-relevant variants in genes associated with cardiac channelopathies and cardiomyopathies.

CONCLUSION: Our study indicates that individuals presenting with VT either secondary to CHD, DCM or of idiopathic etiology carry multiple rare mutations and potentially pathogenic sequence variants in classical cardiac risk genes in a similar pattern and at a comparable frequency. Molecular genetic testing of patients with life-threatening ventricular arrhythmia with NGS identifies a molecular-genetic cause in a significant proportion of patients.