ArticleJournal of the American Heart Association2016
Further Insights in the Most Common SCN5A Mutation Causing Overlapping Phenotype of Long QT Syndrome, Brugada Syndrome, and Conduction Defect.
Article in Journal of the American Heart Association, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 57 citations in OpenAlex.
- Ventricular conduction is a marker for arrhythmic risk in SCN5A-E1784K overlap sodium channel disease.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 · 2026Observational
- Clinical Spectrum of Arrhythmogenic Entities in Spanish Children Carrying DeleteriousInternational journal of molecular sciences · 2026Article
- Phenotypic expression of rare progressive cardiac conduction disease variants in the general population.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
- A Novel Bradycardia-Associated Variant inBiomedicines · 2025Article
- Unconventional diagnosis of bradyarrhythmic syncope in Brugada syndrome: a case report.European heart journal. Case reports · 2024Article
- More than 30 years of Brugada syndrome: a critical appraisal of achievements and open issues.Herzschrittmachertherapie & Elektrophysiologie · 2024Review
- Human Genetics of Cardiac Arrhythmias.Advances in experimental medicine and biology · 2024Review
- Multi-site validation of a functional assay to adjudicatemedRxiv : the preprint server for health sciences · 2023Article
- Functional Characterisation of the RareInternational journal of molecular sciences · 2023Article
- Brugada Syndrome: From Molecular Mechanisms and Genetics to Risk Stratification.International journal of molecular sciences · 2023Review
- Development of automated patch clamp assays to overcome the burden of variants of uncertain significance in inheritable arrhythmia syndromes.Frontiers in physiology · 2023Review
- Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias.International journal of molecular sciences · 2022Review
- Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population.Biomedicines · 2022Review
- Article
- Review
- Distinct Features of Probands With Early Repolarization and Brugada Syndromes Carrying SCN5A Pathogenic Variants.Journal of the American College of Cardiology · 2021Article
- iPSC-Cardiomyocyte Models of Brugada Syndrome-Achievements, Challenges and Future Perspectives.International journal of molecular sciences · 2021Review
- A case report of a young patient with both Brugada and long QT3 syndrome: between the hammer and the anvil.European heart journal. Case reports · 2021Article
- Long QT syndrome - Bench to bedside.Heart rhythm O2 · 2021Article
- Evaluating the Use of Genetics in Brugada Syndrome Risk Stratification.Frontiers in cardiovascular medicine · 2021Article
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundPhenotypic overlap of type 3 long QT syndrome (LQT3), Brugada syndrome (BrS), cardiac conduction disease (CCD), and sinus node dysfunction (SND) is observed with SCN5A mutations. SCN5A-E1784K is the most common mutation associated with BrS and LQTS3. The present study examines the genotype-phenotype relationship in a large family carrying SCN5A-E1784K and SCN5A-H558R polymorphism. METHODS AND
resultsClinical work-up, follow-up, and genetic analysis were performed in 35 family members. Seventeen were SCN5A-E1784K positive. They also displayed QTc prolongation, and either BrS, CCD, or both. One carrier exhibited SND. The presence of SCN5A-H558R did not significantly alter the phenotype of SCN5A-E1784K carriers. Fourteen SCN5A-E1784K patients underwent implantable cardioverter-defibrillator (ICD) implantation; 4 developed VF and received appropriate ICD shocks after 8±3 months of follow-up. One patient without ICD also developed VF after 6.7 years. These 5 cases carried both SCN5A-E1784K and SCN5A-H558R. Functional characterization was achieved by expressing SCN5A variants in TSA201 cells. Peak (INa,P) or late (INa,L) sodium currents were recorded using whole-cell patch-clamp techniques. Co-expression of SCN5A-E1784K and SCN5A-WT reduced INa,P to 70.03% of WT, shifted steady-state inactivation by -11.03 mV, and increased INa,L from 0.14% to 1.86% of INa,P. Similar changes were observed when SCN5A-E1784K was co-expressed with SCN5A-H558R.
conclusionsWe demonstrate a strong genotype-phenotype correlation with complete penetrance for BrS, LQTS, or CCD in the largest family harboring SCN5A-E1784K mutation described so far. Phenotype of LQTS is present during all decades of life, whereas CCD develops with increasing age. Phenotypic overlap may explain the high event rate in carriers.
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