ArticleEuropean heart journal2021
Functionally validated SCN5A variants allow interpretation of pathogenicity and prediction of lethal events in Brugada syndrome.
Article in European heart journal, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 2 of them syntheses that pooled it.
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Who cites it
37 citing papers in PubMed, 2 syntheses or guidelines pooled it, 75 citations in OpenAlex.
- Multiparametric models for predicting major arrhythmic events in Brugada syndrome: a systematic review and critical appraisal.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2025Pooled it
- The SCN5A Gene Is a Predictor of Phenotype Severity in Brugada Syndrome: A Comprehensive Literature Review.Medical principles and practice : international journal of the Kuwait University, Health Science Centre · 2023Pooled it
- Automated patch clamp data improve variant classification and penetrance stratification for SCN5A-Brugada syndrome.European heart journal · 2026Article
- Brugada Syndrome: an exemplar for the genomic basis of sudden death.European journal of human genetics : EJHG · 2026Review
- Phenotypic Severity ofCirculation. Arrhythmia and electrophysiology · 2026Article
- Contemporary Perspectives on J-Wave Syndromes: An Expert Consensus Statement.Journal of arrhythmia · 2026Article
- Characterization of the R893C NaFrontiers in cardiovascular medicine · 2026Article
- Predictive value of Shanghai score system in patients with drug-induced type 1 Brugada electrocardiographic pattern.Clinical research in cardiology : official journal of the German Cardiac Society · 2025Article
- SCN5A mutation-associated sick sinus syndrome revealed by atrial flutter in a pediatric patient.Journal of cardiology cases · 2025Article
- Clinical Features of Brugada Syndrome Patients With SCN5A Variants.Journal of cardiovascular electrophysiology · 2025Article
- Effectiveness of resveratrol in inducing adeno-associated virus as a potential definitive therapy for SCN5A mutation in Brugada syndrome: a narrative review.The Egyptian heart journal : (EHJ) : official bulletin of the Egyptian Society of Cardiology · 2025Review
- SCN5A variant type-dependent risk prediction in Brugada syndrome.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2025Article
- Spontaneous type 1 ECG and arrhythmic risk in Brugada syndrome: A meta-analysis of adjusted time-to-event data.Heart rhythm O2 · 2025Article
- Article
- ParSE-seq: a calibrated multiplexed assay to facilitate the clinical classification of putative splice-altering variants.Nature communications · 2024Article
- Multiplexed Assays of Variant Effect and Automated Patch-clamping ImprovemedRxiv : the preprint server for health sciences · 2024Article
- Rare GPR37L1 Variants Reveal Potential Association between GPR37L1 and Disorders of Anxiety and Migraine.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Variable Penetrance and Expressivity of a Rare Pore Loss-of-Function Mutation (p.L889V) of Nav1.5 Channels in Three Spanish Families.International journal of molecular sciences · 2024Article
- More than 30 years of Brugada syndrome: a critical appraisal of achievements and open issues.Herzschrittmachertherapie & Elektrophysiologie · 2024Review
- Article
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29 authors at 15 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsThe 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
resultsUsing 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.
conclusionIn 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.
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