Loss-of-function variants in the cardiac Kv11.1 channel as a genetic biomarker for SUDEP

Soh, M. S.; .Bagnall, R. D.; Bennett, M. F.; Bleakley, L. E.; Mohamed Syazwan, E. S.; Phillips, A. M.; Chiam, M. D. F.; McKenzie, C. E.; Hildebrand, M.; Crompton, D.; Bahlo, M.; Semsarian, C.; Scheffer, I. E.; Berkovic, S. F.; Reid, C. A.

doi:10.1101/2021.03.19.436102

bioRxiv · 10.1101/2021.03.19.436102

Loss-of-function variants in the cardiac Kv11.1 channel as a genetic biomarker for SUDEP

Soh, M. S.·.Bagnall, R. D.·Bennett, M. F.·Bleakley, L. E.·Mohamed Syazwan, E. S.·Phillips, A. M.·Chiam, M. D. F.·McKenzie, C. E.·Hildebrand, M.·Crompton, D.·Bahlo, M.·Semsarian, C.·Scheffer, I. E.·Berkovic, S. F.·Reid, C. A.

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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 individuals SUDEP risk.

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Soh, M. S., .Bagnall, R. D., Bennett, M. F., Bleakley, L. E., Mohamed Syazwan, E. S., Phillips, A. M., Chiam, M. D. F., McKenzie, C. E., Hildebrand, M., Crompton, D., Bahlo, M., Semsarian, C., Scheffer, I. E., Berkovic, S. F., Reid, C. A.. 2021-03-19. Loss-of-function variants in the cardiac Kv11.1 channel as a genetic biomarker for SUDEP. https://doi.org/10.1101/2021.03.19.436102

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