Pathogenic loss-of-function KCNH2 variants may predispose individuals to both cardiac arrest and respiratory failure following seizures, increasing the risk of Sudden Unexpected Death in Epilepsy.
Pathogenic KCNH2 variants may contribute to SUDEP risk through combined cardiac and autonomic/respiratory dysfunction, highlighting their potential as a biomarker for risk stratification.
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 cardiorespiratory centres, where its impairment may compromise autonomic function, including breathing. Therefore, changes in Kv11.1 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 Kv11.1 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.
“We discovered that the loss-of-function KCNH2 variants play a more significant role in SUDEP than previously known. We found that common loss-of-function variants of this gene were expressed three times higher in a cohort who had experienced SUDEP compared to an epilepsy cohort who hadn't. This increased to 11 times higher for rarer forms of these variants which we found to disrupt ion channel function even more drastically.”
Lee et al. (Wed,) conducted a review in Sudden Unexpected Death in Epilepsy (SUDEP). Loss-of-function KCNH2 variants was evaluated. Pathogenic loss-of-function KCNH2 variants may predispose individuals to both cardiac arrest and respiratory failure following seizures, increasing the risk of Sudden Unexpected Death in Epilepsy.