Loss-of-function variants in the cardiac K_v11.1 channel as a genetic biomarker for SUDEP

Abstract

ObjectiveTo compare the frequency and impact on 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.ResultsKCNH2 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 three-fold 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.ConclusionsThese data show that loss-of-function KCNH2 variants are enriched in SUDEP patients and suggest 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.

Rare sudden unexpected death in epilepsy SCN5A variants cause changes in channel function implicating cardiac arrhythmia as a cause of death

“…6,7 Recently, we reported that KCNH2 variants that cause loss of function are ~3-fold enriched in patients with SUDEP when compared to an aged epilepsy population that has "escaped" SUDEP. 8 This raises the possibility that 'arrhythmogenic variants' could act as genetic biomarkers for SUDEP risk in patients with epilepsy. Genetic screening in epilepsy is becoming more common, providing an opportunity to identify such variants, which may carry management implications, such as increased surveillance of patients in sleep.…”

“…7 Recently, we reported that loss-of-function KCNH2 variants are enriched in a SUDEP population compared to an aged patient population with epilepsy that served as controls, as they have effectively "escaped" SUDEP. 8 Loss-of-function KCNH2 is a well-established risk factor for long-QT syndrome (LQTS), which increases the risk of "torsades de pointes," a type of ventricular tachycardia that triggers cardiac arrest. 9 This suggests a model in which genetic risk factors that predispose to cardiac arrhythmia may contribute to SUDEP risk in certain epilepsy patients.…”

“…Variants in genes associated with cardiac arrhythmias occur in up to 15% of SUDEP cases 7 . Recently, we reported that loss‐of‐function KCNH2 variants are enriched in a SUDEP population compared to an aged patient population with epilepsy that served as controls, as they have effectively “escaped” SUDEP 8 . Loss‐of‐function KCNH2 is a well‐established risk factor for long‐QT syndrome (LQTS), which increases the risk of “torsades de pointes,” a type of ventricular tachycardia that triggers cardiac arrest 9 .…”