Abstract
ObjectiveTo compare the frequency and impact on the channel function of KCNH2 variants in SUDEP patients with epilepsy controls comprising patients older than 50 years, a group with low SUDEP risk, and establish loss‐of‐function KCNH2 variants as predictive biomarkers of SUDEP risk.MethodsWe searched for KCNH2 variants with a minor allele frequency of <5%. Functional analysis in Xenopus laevis oocytes was performed for all KCNH2 variants identified.Results KCNH2 variants were found in 11.1% (10/90) of SUDEP individuals compared to 6.0% (20/332) of epilepsy controls (p = 0.11). Loss‐of‐function KCNH2 variants, defined as causing >20% reduction in maximal amplitude, were observed in 8.9% (8/90) SUDEP patients compared to 3.3% (11/332) epilepsy controls suggesting about threefold enrichment (nominal p = 0.04). KCNH2 variants that did not change channel function occurred at a similar frequency in SUDEP (2.2%; 2/90) and epilepsy control (2.7%; 9/332) cohorts (p > 0.99). Rare KCNH2 variants (<1% allele frequency) associated with greater loss of function and an ~11‐fold enrichment in the SUDEP cohort (nominal p = 0.03). In silico tools were unable to predict the impact of a variant on function highlighting the need for electrophysiological analysis.InterpretationThese data show that loss‐of‐function KCNH2 variants are enriched in SUDEP patients when compared to an epilepsy population older than 50 years, suggesting that cardiac mechanisms contribute to SUDEP risk. We propose that genetic screening in combination with functional analysis can identify loss‐of‐function KCNH2 variants that could act as biomarkers of an individual’s SUDEP risk.
Highlights
People with epilepsy have a two to threefold increased risk of premature mortality, with Sudden Unexpected Death in Epilepsy (SUDEP) the most common cause of death.[1]
Our combined cohorts of 90 unrelated SUDEP patients were recruited from the epilepsy genetics research program in Melbourne, Australia, during life, or from coronial cases investigated at the Departments of Forensic Medicine in New South Wales, Victoria, Queensland, and South Australia, as previously described.[16,18]
Whether other genetic risk factors contribute to SUDEP risk is less clear
Summary
People with epilepsy have a two to threefold increased risk of premature mortality, with Sudden Unexpected Death in Epilepsy (SUDEP) the most common cause of death.[1]. A systematic retrospective analysis of 10 SUDEP deaths in the Incidence and Mechanisms of Cardiorespiratory Arrests in Epilepsy Monitoring Units (MORTEMUS) revealed that seizure-mediated terminal apnea always preceded terminal asystole.[7] The patient cohort in this study was small and involved individuals who were undergoing long-term video-EEG monitoring, implying refractory epilepsy. These cases may, not be representative of all individuals with SUDEP. Aside from seizure severity, the presence of abnormal cardiac rhythms has been implicated in SUDEP risk.[8,9] Both human and animal studies show that seizure-mediated changes in cardiac electrophysiology occur, including seizure-driven cortical autonomic dysfunction and longerterm altered cardiac ion channel expression.[10,11] Patients with epilepsy have an increased risk of sudden cardiac death.[12,13,14] genetic studies have found variants in genes associated with cardiac arrhythmia syndromes in SUDEP cases, including genes that cause long QT syndrome (LQTS).[9,15,16,17,18,19]
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