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.

KCNH2 中的突变可导致长 QT 综合征 2 型。观察到这种通道病的不同疾病表现与蛋白质内突变的位置和类型有关，使预测患者风险的工作复杂化。在这里，我们证明了源自等基因人类诱导多能干细胞 (hiPSC-CM) 的心肌细胞的表型差异，这些细胞经过基因编辑以在离子通道的孔或尾部区域内含有突变。电生理分析证实，这些突变延长了 hiPSC-CM 的复极化，单层培养物中突变之间的差异很明显。阻断 hERG 通道显示孔环突变赋予对心律失常事件更大的易感性。这些发现表明，与KCNH2相关的细微表型差异在基因匹配的条件下，hiPSC-CM 可以捕获突变。此外，结果支持 hiPSC-CM 作为评估人类个体KCNH2突变潜在严重程度的有力候选者，这可以促进患者风险分层。