Isogenic Sets of hiPSC-CMs Harboring Distinct KCNH2 Mutations Differ Functionally and in Susceptibility to Drug-Induced Arrhythmias

Mutations in KCNH2 can lead to long QT syndrome type 2. Variable disease manifestation observed with this channelopathy is associated with the location and type of mutation within the protein, complicating efforts to predict patient risk. Here, we demonstrated phenotypic differences in cardiomyocytes derived from isogenic human induced pluripotent stem cells (hiPSC-CMs) genetically edited to harbor mutations either within the pore or tail region of the ion channel. Electrophysiological analysis confirmed that the mutations prolonged repolarization of the hiPSC-CMs, with differences between the mutations evident in monolayer cultures. Blocking the hERG channel revealed that the pore-loop mutation conferred greater susceptibility to arrhythmic events. These findings showed that subtle phenotypic differences related to KCNH2 mutations could be captured by hiPSC-CMs under genetically matched conditions. Moreover, the results support hiPSC-CMs as strong candidates for evaluating the underlying severity of individual KCNH2 mutations in humans, which could facilitate patient risk stratification. [Display omitted] •Mutation-specific differences detected in hiPSC-CMs with same genetic background•APD and FPD in the hERG pore variant hiPSC-CMs more prolonged than the tail variant•The pore variant was also more susceptible to drug-induced arrhythmic events•Potential strategy to determine KCNH2 mutation-specific arrhythmic risk In this article, Davis and colleagues showed that, by studying on the same genetic background different KCNH2 mutations that can cause LQT2, subtle molecular and electrophysiological differences related to the specific mutation were captured by the corresponding hiPSC-CMs; raising the possibility of using hiPSC-CMs to model mutation-location differences observed in LQT2 patients and thereby assist in patient risk stratification.