ArticleEuropace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology2026
Identification and functional assessment of a KCNH2 compound heterozygosity in a patient with presumed idiopathic ventricular fibrillation ascertains the diagnosis of long QT syndrome type 2.
Article in Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
BACKGROUND AND
aimsThe KCNH2 (hERG) gene encodes the Kv11.1 protein, the pore-forming subunit of the rapid delayed rectifier potassium channel, which plays a key role in cardiac repolarization. We aimed to investigate the function of two Kv11.1 variants in trans, S1021Qfs*98 and A228V, identified in a patient suffering from idiopathic ventricular fibrillation (VF).
methodsA detailed clinical and genetic investigation was followed by functional analysis using the whole-cell patch clamp technique, western blot, and mathematical simulations in a human ventricular cell model.
resultsIn comparison with wild type, the current was decreased by 69.5 and 69.2% in S1021Qfs*98 and S1021Qfs*98/A228V, respectively, which agreed well with a significant decrease in the expression of S1021Qfs*98 channels, but no differences were observed in A228V. The voltage dependence of activation and inactivation and the time course of activation and deactivation remained unchanged. Minor changes were observed in the time course of inactivation and recovery from inactivation in S1021Qfs*98 and S1021Qfs*98/A228V. Arrhythmogenesis based on early afterdepolarizations (EADs) at rest, provoked by hypokalemia, and during β-adrenergic stimulation was suggested by simulations in a human ventricular cell model.
conclusionTo conclude, A228V is a benign variant, whereas S1021Qfs*98 exhibits a loss-of-function defect and dominant negativity. EADs-related arrhythmogenesis was predicted, which explains the pathogenic phenotype of the proband carrying both these variants and experiencing repetitive VF episodes. Based on the findings, we reclassify S1021Qfs*98 as a pathogenic, LQT2-associated variant. The data highlight the importance of functional analysis for the correct management of patients with idiopathic VF and genetic variants.
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