Functionally validated SCN5A variants allow interpretation of pathogenicity and prediction of lethal events in Brugada syndrome

Abstract

Aims The prognostic value of genetic variants for predicting lethal arrhythmic events (LAEs) in Brugada syndrome (BrS) remains controversial. We investigated whether the functional curation of SCN5A variations improves prognostic predictability. Methods and results Using a heterologous expression system and whole-cell patch clamping, we functionally characterized 22 variants of unknown significance (VUSs) among 55 SCN5A mutations previously curated using in silico prediction algorithms in the Japanese BrS registry (n = 415). According to the loss-of-function (LOF) properties, SCN5A mutation carriers (n = 60) were divided into two groups: LOF-SCN5A mutations and non-LOF SCN5A variations. Functionally proven LOF-SCN5A mutation carriers (n = 45) showed significantly severer electrocardiographic conduction abnormalities and worse prognosis associated with earlier manifestations of LAEs (7.9%/year) than in silico algorithm-predicted SCN5A carriers (5.1%/year) or all BrS probands (2.5%/year). Notably, non-LOF SCN5A variation carriers (n = 15) exhibited no LAEs during the follow-up period. Multivariate analysis demonstrated that only LOF-SCN5A mutations and a history of aborted cardiac arrest were significant predictors of LAEs. Gene-based association studies using whole-exome sequencing data on another independent SCN5A mutation-negative BrS cohort (n = 288) showed no significant enrichment of rare variants in 16 985 genes including 22 non-SCN5A BrS-associated genes as compared with controls (n = 372). Furthermore, rare variations of non-SCN5A BrS-associated genes did not affect LAE-free survival curves. Conclusion In vitro functional validation is key to classifying the pathogenicity of SCN5A VUSs and for risk stratification of genetic predictors of LAEs. Functionally proven LOF-SCN5A mutations are genetic burdens of sudden death in BrS, but evidence for other BrS-associated genes is elusive.

The year in cardiovascular medicine 2021: arrhythmias

“…Importantly, non-LOF SCN5A variation carriers ( n = 15) exhibited no LAEs during the follow-up period. 53 Multivariate analysis demonstrated that only LOF SCN5A mutations and a history of aborted cardiac arrest were significant predictors of LAEs. 53 Rare variations of non-SCN5A BrS-associated genes did not affect LAE-free survival curves.…”

Pathogenesis and Management of Brugada Syndrome: Recent Advances and Protocol for Umbrella Reviews of Meta-Analyses in Major Arrhythmic Events Risk Stratification

“…SCN5A gene variants may be important predictors of fatal events in BrS and valuable in risk stratification [ 57 ]. Loss-of-function SCN5A mutations have shown association with prolonged ECG conduction parameters (P wave or QRS durations) and increased occurrence of lethal arrhythmic events compared to the non-loss-of-function SCN5A mutations or SCN5A(−) BrS patients [ 57 ].…”

How Functional Genomics Can Keep Pace With VUS Identification

“…Extrapolating their patch clamp data has the potential to reduce the total Nav1.5 VUS functional burden by at least 75%. This assay was further validated in a study of 22 Nav1.5 variants showing patch clamp data to be an excellent predictor of pathogenicity and lethal cardiac arrhythmias in Brugada Syndrome ( 63 ).…”