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While rare mutations in ion channel genes are primarily responsible for inherited cardiac arrhythmias, common genetic variants are also an important contributor to the clinical heterogeneity observed among mutation carriers. The common single nucleotide polymorphism (SNP) KCNH2-K897T is associated with QT interval duration, but its influence on the disease phenotype in patients with long QT syndrome type 2 (LQT2) remains unclear. Human induced pluripotent stem cells (hiPSCs), coupled with advances in gene editing technologies, are proving an invaluable tool for modeling cardiac genetic diseases and identifying variants responsible for variability in disease expressivity. In this study, we have used isogenic hiPSC-derived cardiomyocytes (hiPSC-CMs) to establish the functional consequences of having the KCNH2-K897T SNP in  cis - or  trans -orientation with LQT2-causing missense variants either within the pore-loop domain (KCNH2 A561T/WT ) or tail region (KCNH2 N996I/WT ) of the potassium ion channel, human ether-a-go-go-related gene (hERG). When KCNH2-K897T was on the same allele ( cis ) as the primary mutation, the hERG channel in hiPSC-CMs exhibited faster activation and deactivation kinetics compared to their  trans -oriented counterparts. Consistent with this, hiPSC-CMs with KCNH2-K897T in  cis  orientation had longer action and field potential durations. Furthermore, there was an increased occurrence of arrhythmic events upon pharmacological blocking of hERG. Collectively, these results indicate that the common polymorphism KCNH2-K897T differs in its influence on LQT2-causing  KCNH2  mutations depending on whether it is present in  cis  or  trans . This study corroborates hiPSC-CMs as a powerful platform to investigate the modifying effects of common genetic variants on inherited cardiac arrhythmias and aids in unraveling their contribution to the variable expressivity of these diseases.

The Linkage Phase of the Polymorphism KCNH2-K897T Influences the Electrophysiological Phenotype in hiPSC Models of LQT2