The Role of Loss-of-Function KCNH2 Variants in Cardiac Arrhythmias, Seizures and the Risk of Sudden Unexpected Death...

Sudden Unexpected Death in Epilepsy (SUDEP) is the leading cause of mortality in patients in epilepsy, yet its underlying mechanisms are poorly understood. Emerging evidence suggests a significant role for genetic factors that influence cardiac function in SUDEP risk, particularly loss-of-function variants in KCNH2, which encodes the K_v11.1 potassium channel. K_v11.1 channels are expressed in both cardiac and neuronal tissues. Pathogenic KCNH2 variants are strongly associated with cardiac arrhythmias leading to increased risk of sudden cardiac death. There is also evidence that KCNH2 variants can influence seizure susceptibility. Furthermore, K_v11.1 is expressed in brain autonomic and cardiorespiratory centres, where its impairment may compromise autonomic function, including breathing. Therefore, changes in K_v11.1 channel function in both central and cardiac tissues could potentially contribute to increased SUDEP risk. In this review, we explore the potential dual contribution of K_v11.1 channel dysfunction to SUDEP risk. We hypothesise how this dual-system vulnerability may predispose individuals with pathogenic KCNH2 variants to both cardiac arrest and respiratory failure following seizures. By integrating genetic, electrophysiological, and neuroanatomical evidence to support our hypothesis, this review presents a multidisciplinary framework for understanding SUDEP and highlights the potential of pathogenic KCNH2 variants as a biomarker for risk and targeted intervention.