Published online May 26, 2026. doi: 10.4252/wjsc.v18.i5.117584
Revised: January 17, 2026
Accepted: March 17, 2026
Published online: May 26, 2026
Processing time: 166 Days and 0.1 Hours
Congenital long QT syndrome (LQTS) is an inherited arrhythmia linked to a high risk of sudden cardiac death. LQTS type 2 is mainly caused by KCNH2 mutations. Even among carriers of the same pathogenic KCNH2 variant, clinical manifestations and disease severity vary, with the underlying mechanisms remaining unclear.
To investigate mechanisms underlying variable clinical severity among carriers of the same KCNH2 mutation using patient-specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs).
iPSCs were generated from the peripheral blood mononuclear cells of a family trio: A symptomatic proband, an asymptomatic carrier mother, and a mutation-negative father. Using nonintegrating Sendai virus, these iPSCs were then differentiated into cardiomyocytes using a monolayer-based protocol. The functional properties of the iPSC-CMs were assessed using patch-clamp recordings, calcium imaging, and multi-electrode array recordings.
The proband iPSC-CMs exhibited a significant prolongation of action potential duration compared with the mother and father iPSC-CMs. Both the proband and mother iPSC-CMs, carrying the heterozygous KCNH2 p.Y427H variant, demonstrated a significant reduction in the rapid delayed rectifier potassium current, consistent with a loss-of-function mutation. Notably, the proband iPSC-CMs showed an enhanced L-type calcium current and exaggerated calcium transients. These abnormalities were accompanied by increased arrhythmogenicity, manifesting as early afterdepolarizations and triggered arrhythmias. Treatment with nifedipine partially restored repolarization and effectively suppressed all these arrhythmic events.
Calcium dysregulation is a critical modifier of phenotypic severity. Patient-specific iPSC-CMs provide a powerful platform for modeling intra-familial phenotypic variability in LQTS type 2, highlighting their potential for individualized risk assessment and therapeutic evaluation.
Core Tip: Using induced pluripotent stem cell-derived cardiomyocytes, we modeled a family with congenital long QT syndrome type 2 caused by a KCNH2 variant to explain why clinical severity differs among carriers. Although both affected individuals showed a reduced rapid delayed rectifier potassium current, only the symptomatic proband exhibited calcium handling abnormalities, increased L-type calcium current, and spontaneous arrhythmias. Pharmacological correction with nifedipine suppressed these arrhythmias. This work highlights calcium dysregulation as a key modifier of disease severity and supports the use of patient-specific induced pluripotent stem cell-derived cardiomyocytes for personalized risk assessment and therapy selection.