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

Abstract

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 Kv11.1 potassium channel. Kv11.1 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, Kv11.1 is expressed in brain autonomic and cardior..