Functional evaluation of the tachycardia patient‐derived iPSC cardiomyocytes carrying a novel pathogenic SCN5A variant

Tachycardia is characterized by high beating rates that can lead to life‐threatening fibrillations. Mutations in several ion‐channel genes were implicated with tachycardia; however, the complex genetic contributors and their modes of action are still unclear. Here, we investigated the influence of an SCN5A gene variant on tachycardia phenotype by deriving patient‐specific iPSCs and cardiomyocytes (iPSC‐CM). Two tachycardia patients were genetically analyzed and revealed to inherit a heterozygous p.F1465L variant in the SCN5A gene. Gene expression and immunocytochemical analysis in iPSC‐CMs generated from patients did not show any significant changes in mRNA levels of SCN5A or gross NaV1.5 cellular mislocalization, compared to healthy‐derived iPSC‐CMs. Electrophysiological and contraction imaging analysis in patient iPSC‐CMs revealed intermittent fibrillation‐like states, occasional arrhythmic events, and sustained high‐paced contractions that could be selectively reduced by flecainide treatment. The patch‐clamp analysis demonstrated a negative shift in the voltage‐dependent activation at the patient‐derived iPSC‐CMs compared to the healthy control line, suggestive of a gain‐of‐function activity associated with the SCN5A+/p.F1465L variant. Our patient‐derived iPSC‐CM model recapitulated the clinically relevant characteristics of tachycardia associated with a novel pathogenic SCN5A+/p.F1465L variant leading to altered Na+ channel kinetics as the likely mechanism underlying high excitability and tachycardia phenotype.