KCNH2LQT2

KCNH2 is the gene that encodes the alpha subunit of the hERG potassium channel (Kv11.1) in the heart. It is located on chromosome 7q36.1 and plays a critical role in repolarization by carrying the rapid delayed rectifier potassium current (IKr) during phase 3 of the cardiac action potential. Proper trafficking and function of hERG channels are essential for normal QT intervals.

Pathogenic variants in KCNH2 cause the Long QT syndrome type 2 (LQT2), an autosomal dominant inherited arrhythmia syndrome. More than 1,000 variants have been described; most lead to loss of hERG channel function, either by reducing channel expression on the cell surface or by altering the pore that conducts potassium. This reduces IKr, prolonging ventricular repolarization and the QT interval. Penetrance is incomplete and expressivity varies.

Clinically, LQT2 presents with episodes of syncope or sudden cardiac death due to torsades de pointes, often triggered by emotional stress or sudden loud noises, and can be detected by a prolonged QTc on ECG. Diagnosis relies on ECG findings and confirmation by genetic testing identifying a pathogenic KCNH2 variant; cascade testing in relatives is common.

Management focuses on reducing arrhythmic risk: beta-blocker therapy as first line, avoidance of QT-prolonging drugs, correction of electrolyte abnormalities, and consideration of implantable cardioverter-defibrillator in high-risk individuals or those with syncope despite treatment. Left cardiac sympathetic denervation may be considered in selected cases.

Acquired LQTS can also result from drugs that block hERG channels, highlighting the channel’s central role in repolarization. Ongoing research seeks better genotype-phenotype correlations and targeted therapies for KCNH2-related LQT2.