KCNH2 regulates developmental gene networks and cell fate in human pluripotent stem cells

KCNH2 encodes the voltage-gated potassium channel hERG1, which conducts the rapid delayed rectifier current (IKr) that is essential for cardiac repolarization. Loss-of-function KCNH2 variants or pharmacological inhibition of hERG1 cause congenital long QT syndrome type 2 and acquired long QT syndrome, respectively. KCNH2 variants are also associated with intrauterine fetal death and sudden infant death syndrome, yet the contribution of KCNH2 in early human development remains unclear. To explore this, we generated a KCNH2-/- human embryonic stem cell (hESC) line, which exhibited reduced proliferation and increased cell death at high confluency compared to isogenic controls. Transcriptomic analysis revealed widespread dysregulation of developmental genes, indicating impaired differentiation and altered cardiovascular gene networks. Pathways involved in calcium homeostasis, cell motility, and chemotaxis were also disrupted. These findings identify KCNH2 as a bioelectric modulator of early human developmental gene networks, extending its function beyond cardiac electrophysiology and informing congenital disease mechanisms.