Low-frequency SCN5A variants and reduced functional scores associate with adverse arrhythmic outcomes
R Griffiths, M Futema, M Specterman, D Johnson, Y Sharhorodska, D Roden, J Vandenberg, C A Ng, A Glazer, E BehrAbstract
Background
Rare variants in SCN5A, encoding the alpha subunit of the voltage gated cardiac sodium channel, confer arrhythmic risk in Brugada Syndrome. Commoner, but low-frequency SCN5A variants may partly explain the Brugada Syndrome phenotype but their association with arrhythmic risk has not previously been explored. An automated patch clamp assay has previously assayed loss-of-function effect on peak sodium current of SCN5A variants of uncertain significance.
Purpose
To determine whether low-frequency SCN5A variants and z-scores for the in vitro SCN5A loss-of-function phenotype associate with adverse arrhythmic outcomes.
Methods
SCN5A genotypes were established for 78,069 participants who underwent whole genome sequencing as part of the 100,000 Genomes Project, a mixed rare disease and cancer cohort with longitudinal follow-up from the United Kingdom. Adverse arrhythmic outcome data were extracted from National Health Service admitted patient care records and matched to participants. Outcome data were pooled into clinically relevant categories and combined to form a primary composite outcome, consisting of cardiac arrest, sudden death and ventricular arrhythmia. Differences in adverse arrhythmic outcomes between participants with selected low-frequency variants (minor allele frequency < 0.01 and ≥ 0.001) with available z-scores (p.S216L, p.R34C, p.P2005A, p.S524Y, p.V1950L) and wild-type participants were evaluated using logistic regression. Amongst participants harbouring one of 116 SCN5A variants with a z-score value, z-score and its association with adverse arrhythmic outcome was assessed using logistic regression and time-to-event analyses.
Results
Carriers of p.S216L (n = 190, z-score -2.64) were shown to be at a higher risk of the pooled outcome of cardiac arrest and sudden death (odds ratio = 2.45, 95% confidence interval [CI] 0.96-5.07; p-value = 0.03). p.V1950L variant carriers (n = 82, z-score -0.31) had an increased risk of the composite outcome (odds ratio = 2.89, 95% CI 1.01-6.48; p-value = 0.02). No statistically significant associations between adverse arrhythmic outcomes and the p.R34C, p.P2005A and p.S524Y variants (with z-scores of 0.45, 0.45 and -1.51 respectively) were observed. Across all 116 variants with a z-score value, z-scores of -4 and below, indicating severe loss-of-function, were associated with an increased risk of the composite outcome (hazard ratio = 9.95, 95% CI 4.14-23.94; p-value < 0.0001, see Figure 1).
Conclusions
Low-frequency SCN5A variants and the degree of in vitro loss-of-function are associated with adverse arrhythmic outcomes. These findings support incorporating both variant frequency and quantitative functional data into arrhythmic risk stratification frameworks. Validation in larger, independent cohorts will be required to confirm clinical utility in Brugada Syndrome and broader populations.