NEXT GENERATION SEQUENCING FOR INHERITED CARDIOMYOPATHIES: IMPLICATIONS FOR CLINICAL PRACTICES

Inherited cardiomyopathies (ICs) are the leading cause of sudden death in young adults. Given their marked clinical and genetic heterogeneity, sequencing of multiple IC genes is needed to detect the underlying genetic cause and facilitate clinical interventions. We sought to implement a Next Generation Sequencing (NGS)-based assay for the molecular diagnosis of diverse ICs and assess its diagnostic utility in a large heterogeneous cohort of patients. We validated an NGS-based assay that simultaneously analyzes 45 IC genes in a retrospective cohort of 72 individuals, and assessed its diagnostic utility in a prospective cohort of 993 individuals with a clinical diagnosis or suspicion of IC. The 45 IC genes were sequenced with high average read depth (∼500X) and 99.78% of the targeted regions were covered at ≥ 20X. All variants were detected in their correct zygosity, achieving an analytical sensitivity of 100% and a false positive rate of 0%. The validated NGS assay was highly reproducible and offered 45% reduction in cost as compared to Sanger Sequencing (SS). The expansion of gene panels resulted in only a marginal increase in diagnostic yield while the rate of inconclusive findings increased significantly. We show that our NGS-based diagnostic assay has a robust analytical performance and offers highly accurate, cost and time efficient solution for the molecular diagnosis of ICs. We discuss the implications of our results for clinical practice.