Genetic epidemiology of ventricular tachycardia in patients with cardiomyopathy in Kazakhstan: a targeted sequencing study

Ventricular tachycardia (VT) is a common complication in cardiac disorders of different etiology such as coronary heart disease (CHD) and cardiomyopathies. We hypothesized that the underlying molecular mechanism, independent of disease etiology, might originate from a common overlapping pattern of genetic variants in cardiac disease-related genes. Aim: to investigate genetic basis of VT in patients with cardiomyopathy in Kazakhstan using targeted NGS (design of new HaloPlex gene panel). Material and methods. Using a customized HaloPlex Target Enrichment System? (Agilent Technologies, USA) 96 cardiomyopathy associated candidate-genes were enriched and then sequenced on HiSeq2000 platform using 2x150bp paired-end standard sequencing conditions in DNA of 95 patients diagnosed with sporadic (64/95) or familial (26/95) cardiomyopathies (dilated cardiomyopathy (DCM): 37.3%, idiopathic ventricular tachycardia (iVT): 38.9%, CHD with severe episodes of VT: 24.2%, and others: 3%). Results: The candidate gene library design covers a total target region of 463.767kbp with 406.062 analyzable target bases including all exonic and proximal intronic (+/-10bp) sequence and representing by 2,017 target loci. The mean coverage of all 95 samples at the target loci was 707.62-fold. Targeted sequencing and stepwise filtering of the annotated variants identified a total of 319 unique variants in 74 genes totaling up in 475 variants for the overall study group (HGMD listed). More than 50% of the patients carried at least two mutations, irrespective of the clinical phenotype. Furthermore, 215 private (unique) non-synonymous variants were observed in the patient cohort. Prediction scores of the private variants indicated high probability of disease association. Including the newly identified high-probability variants, each patient carried on average >4.8 genetic variants. Interestingly, statistical evaluation revealed no difference in the frequency of genetic variants (HGMD or rare variants) observed for the CHD and the DCM subgroup. The most abundant mutations of the CHD were observed in MYBPC3, DMD, LAMA2, MYH6 and GAA. PRKAG2 mutations were overrepresented in the CHD subgroup. Conclusion: Our study indicates that the majority of the investigated patients with cardiomyopathies and VT, irrespective of disease phenotype or subgroup carry multiple disease-linked mutations and additional potentially functional rare variants in cardiac disease genes. We thus have to consider a molecular disease-overlap with converging phenotypes.