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Ann Clin Transl Neurol
2021 Jul 01;87:1422-1432. doi: 10.1002/acn3.51381.
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Loss-of-function variants in Kv 11.1 cardiac channels as a biomarker for SUDEP.
Soh MS
,
Bagnall RD
,
Bennett MF
,
Bleakley LE
,
Mohamed Syazwan ES
,
Phillips AM
,
Chiam MDF
,
McKenzie CE
,
Hildebrand M
,
Crompton D
,
Bahlo M
,
Semsarian C
,
Scheffer IE
,
Berkovic SF
,
Reid CA
.
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OBJECTIVE: To 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.
METHODS: We 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.
INTERPRETATION: These 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.
Victorian State Government, #1104831 National Health and Medical Research Council, #1154992 National Health and Medical Research Council, 10915693 National Health and Medical Research Council, #1172897 National Health and Medical Research Council, #1102971 National Health and Medical Research Council, Australian Government National Health and Medical Research Council (NHMRC), Australian Government
Figure 1 Functional analysis of KCNH2 variants from SUDEP patients. (A) Sample recording traces of Kv11.1 wild-type (WT) channels. Insert: cartoon of the voltage protocol applied. (B–G) Sample recording traces of Kv11.1 variant channels (top) and average normalized conductance–voltage relationships (below) comparing Kv11.1 WT and variant channels for (B) R1047L, (C) G924A, (D) G749A, (E) R744X, (F) R176W, and (G) Y54H variants. (H) Average maximal amplitude for each variant. Number in each bar represents the number of independent oocytes recorded for each variant. Black and red dashed lines indicate 100% and 80%, respectively, of maximal current amplitude of Kv11.1WT channel. *p < 0.05, ****p < 0.0001.
Figure 2 Functional analysis of KCNH2 variants from epilepsy control cohort. Sample recording traces of Kv11.1 variant channels (top) and average normalized conductance–voltage relationships (below) comparing Kv11.1 WT and variant channels for (A) A913V (B) G903R, (C) K897R, (D) S871C, (E) T436M, (F) R397H, (G) P347S, (H) D259N (I), A193V, and (J) S140F variants. (K) Average maximal amplitude for each variant in the epilepsy control cohort. Number in each bar represents the number of independent oocytes recorded for each variant. Black and red dashed lines indicate 100% and 80%, respectively, of maximal current amplitude of the Kv11.1 WT channel. *p < 0.05, **p < 0.01.
Figure 3 Biophysical properties of KCNH2 variants from SUDEP cases and epilepsy control population. (A) Average half-maximal voltage of activation for each variant in SUDEP cohort. (B) Average half-maximal voltage of activation for each variant in the epilepsy control cohort. (C) Average slope from the Boltzmann fit for each variant in the SUDEP cohort. (D) Average slope from the Boltzmann fit for each variant in the epilepsy control cohort. Number in each bar represents the number of independent oocytes recorded for each variant. *p < 0.05, **p < 0.01, ****p < 0.0001.
Figure 4 Enrichment of KCNH2 variants in SUDEP and epilepsy control cohorts. (A) KCNH2 variants with less than 5% allele frequency are enriched approximately three times in SUDEP compared to the epilepsy control cohort. (B) Enrichment of rare KCNH2 variants with less than 1% allele frequency is further increased to about 10 times in the SUDEP cohort. *p < 0.05.
FIGURE 1. Functional analysis of KCNH2 variants from SUDEP patients. (A) Sample recording traces of Kv11.1 wildâ€type (WT) channels. Insert: cartoon of the voltage protocol applied. (B–G) Sample recording traces of Kv11.1 variant channels (top) and average normalized conductance–voltage relationships (below) comparing Kv11.1 WT and variant channels for (B) R1047L, (C) G924A, (D) G749A, (E) R744X, (F) R176W, and (G) Y54H variants. (H) Average maximal amplitude for each variant. Number in each bar represents the number of independent oocytes recorded for each variant. Black and red dashed lines indicate 100% and 80%, respectively, of maximal current amplitude of Kv11.1WT channel. *p < 0.05, ****p < 0.0001.
FIGURE 2. Functional analysis of KCNH2 variants from epilepsy control cohort. Sample recording traces of Kv11.1 variant channels (top) and average normalized conductance–voltage relationships (below) comparing Kv11.1 WT and variant channels for (A) A913V (B) G903R, (C) K897R, (D) S871C, (E) T436M, (F) R397H, (G) P347S, (H) D259N (I), A193V, and (J) S140F variants. (K) Average maximal amplitude for each variant in the epilepsy control cohort. Number in each bar represents the number of independent oocytes recorded for each variant. Black and red dashed lines indicate 100% and 80%, respectively, of maximal current amplitude of the Kv11.1 WT channel. *p < 0.05, **p < 0.01.
FIGURE 3. Biophysical properties of KCNH2 variants from SUDEP cases and epilepsy control population. (A) Average halfâ€maximal voltage of activation for each variant in SUDEP cohort. (B) Average halfâ€maximal voltage of activation for each variant in the epilepsy control cohort. (C) Average slope from the Boltzmann fit for each variant in the SUDEP cohort. (D) Average slope from the Boltzmann fit for each variant in the epilepsy control cohort. Number in each bar represents the number of independent oocytes recorded for each variant. *p < 0.05, **p < 0.01, ****p < 0.0001.
FIGURE 4. Enrichment of KCNH2 variants in SUDEP and epilepsy control cohorts. (A) KCNH2 variants with less than 5% allele frequency are enriched approximately three times in SUDEP compared to the epilepsy control cohort. (B) Enrichment of rare KCNH2 variants with less than 1% allele frequency is further increased to about 10 times in the SUDEP cohort. *p < 0.05.
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