Brugada Syndrome (BrS)

Overview

Brugada syndrome is an inherited channelopathy characterised by coved ST-segment elevation ≥2 mm with T-wave inversion in the right precordial leads, predisposing to syncope and sudden cardiac death from ventricular fibrillation in the absence of structural heart disease. It is a major cause of SCD in young individuals with structurally normal hearts, accounting for up to 28% of SCDs in this population. Arrhythmias occur predominantly at rest, during sleep, or after large meals — periods of high vagal tone or bradycardia.

Epidemiology

• Prevalence: ~1:2,000 for type 1 ECG pattern; ~1:500 for type 2/3 ECG. Most common in Asia, followed by Europe and the US. (sources/brs-jaccep-2022)
• Prevalence in children is ~1:20,000; phenotypic expression is age-dependent. (sources/brs-jaccep-2022)
• Males account for ~80–90% of diagnosed cases — disparity appears after adolescence (not sex-linked per se, but sex-hormone modulated). (sources/brs-jaccep-2022)
• ~2/3 of patients at diagnosis are asymptomatic; ~1/3 present with syncope or palpitations; SCD can be the first manifestation. (sources/channelopathies-jaha-2025)
• BrS accounts for up to 28% of SCD in structurally normal hearts and ~5–10% of resuscitated cardiac arrest cases. (sources/brs-jaccep-2022)
• Associated conduction abnormalities in some patients: 1st-degree AV block, RBBB, intraventricular conduction delay, sick sinus syndrome. (sources/channelopathies-jaha-2025)

Pathophysiology

• Sodium channel basis: NaV1.5 (encoded by SCN5A) is the predominant cardiac sodium channel. Loss-of-function variants → reduced peak INa → slowed phase 0 upstroke and shortened action potential duration, predominantly in the RVOT epicardium. NaV1.5 function is temperature-dependent — explaining fever-precipitated events. (sources/brs-jaccep-2022)
• Genetics: SCN5A is now curated as definitively disease-causing via the broad "SCN5A-related cardiac rhythm disorder" designation (ClinGen 10/08/2025), identified in only ~20% of BrS patients. ClinGen 2026 disputed/refuting BrS genes: KCNH2 (disputing 06/2025), CACNA1C (disputing 02/2025), CACNB2 (disputing 07/2025), ABCC9 (disputing 10/2025), SCN10A (disputing 09/2025), HCN4 (disputing 11/2017), SCN1B (disputing 11/2017), SCN2B (disputing 11/2017), PKP2 (disputing 11/2017). Refuting: TRPM4 (refuting 12/2025), SCN3B (refuting 12/2025). SLMAP, SEMA3A, SCNN1A additionally identified by Campuzano et al. (2019) but lack ClinGen validation. See concepts/ClinGen-Gene-Disease-Validity. (sources/channelopathies-jaha-2025, sources/arrhythmia-genetics-mgenetik-2025, sources/clingen-summary-2026-05-09, rating: high)
• SCN5A H558R (rs1805124) — epigenetic-genetic modifier of BrS: The common SCN5A polymorphism H558R acts as a genetic modifier of BrS by repairing abnormal channel gating kinetics and improving Nav1.5 membrane trafficking in pathogenic SCN5A mutation carriers, reducing phenotypic severity. Epigenetically, H558R reduces methylation of the SCN5A promoter → increases SCN5A cardiac expression → may prevent VF. Paradoxically, the G allele of H558R is also associated with QTc prolongation in population studies, reflecting its pleiotropic and context-dependent effects on sodium channel function. (sources/genetics-va-fcvm-2022 — medium)
• Polygenic mechanism: GWAS data suggest that multiple common SNPs — not a single gene variant — likely account for the majority of BrS cases. This explains familial clustering without an identifiable pathogenic variant; penetrance in SCN5A-positive families is only ~50%. (sources/brs-jaccep-2022)
  • 21 independent GWAS loci across 12 chromosomal regions (Dababneh 2025 review): Novel validated loci include HEY2 (cardiac transcription factor critical to RVOT development) and MAPRE2 (microtubule-end-binding protein involved in myofilament organisation and cardiac conduction) — extending BrS genetic architecture well beyond ion channel genes. (sources/gwas-arrhythmias-cmp-genes-2025, rating: high)
  • BrS PRS — OR 2.12/SD (Ishikawa 2024): A BrS GWAS-derived PRS predicts spontaneous type 1 ECG pattern and positive sodium channel blocker provocation test with OR 2.12 per SD increase. The European-ancestry BrS PRS achieves similar predictive performance in Japanese BrS patients — unusual cross-ancestry portability compared to most cardiac GWAS. Critically, the PRS does NOT predict lethal arrhythmic events (VF/SCD) — a fundamental dissociation between polygenic susceptibility to the ECG phenotype and true arrhythmic risk that has direct implications for how PRS findings should be communicated to patients and families. (sources/gwas-arrhythmias-cmp-genes-2025)
• Three competing pathophysiological hypotheses (non-mutually exclusive):
  • Depolarization: Fibrosis, inflammatory infiltrates, and reduced connexin-43 in the epicardial RVOT → conduction delay and heterogeneity of depolarization → arrhythmogenic substrate. Supported by histopathology and electroanatomic mapping showing low voltage and fractionated electrograms in the RVOT. (sources/brs-jaccep-2022)
  • Repolarization: Increased outward Ito (carried by Kv4.3, encoded by KCND3; amplitude modulated by KChIP2 β-subunit; regulatory β-subunits KCNE3/MiRP2 and KCNE5/MiRP4 also co-assemble with KCND3 and can increase Ito) during phase 1 of the action potential shortens the AP dome selectively in the RVOT subepicardium (where Ito density is highest) → "all-or-none" loss of AP dome in subepicardium → voltage gradient between epicardium (repolarized) and endocardium (still in plateau) → current of injury (the BrS ECG pattern) → phase 2 re-entry: dome restoration in adjacent epicardial cell provides the trigger for VF. Ito prominence in the atria also contributes to atrial arrhythmias in BrS. KCNE3 Arg99His (GOF): when co-expressed with KCND3, significantly increases Ito current intensity compared to WT — a rare BrS cause. KCNE5 (X-linked, MiRP4, GOF): BrS-associated KCNE5 mutations upregulate Ito when co-expressed with KCND3; also associated with IVF — rare. (sources/brs-jaccep-2022, sources/membrane-potential-physrev-2021, sources/genetics-va-fcvm-2022 — medium)
  • KChIP2 and male predominance: KChIP2 (K⁺ channel-interacting protein 2) is a β-subunit that enhances Kv4.3 trafficking and increases Ito amplitude. KChIP2 expression is significantly higher in males, driven by androgen receptor signalling. This explains why the same SCN5A LOF variant causes manifest BrS predominantly in males — they have higher baseline Ito to begin with, making phase 1 shortening and AP dome loss more likely at any given level of INa reduction. Oestrogen suppresses KChIP2 expression and reduces Ito, partially explaining why premenopausal females are protected. (sources/membrane-potential-physrev-2021)
  • Neural crest: Abnormal cardiac neural crest cell migration → impaired connexin-43 expression → electrical uncoupling in the outflow tract. (sources/channelopathies-jaha-2025)
• A confluence of factors producing a common ECG phenotype is most likely — no single hypothesis is fully reconciled. (sources/brs-jaccep-2022)
• BrS as partial cardiomyopathy: Growing CMR evidence of structural RVOT abnormalities (enlarged ventricular volumes, structural changes) in BrS patients suggests BrS may be part of a cardiomyopathy spectrum where the arrhythmogenic substrate is predominantly or exclusively in the RVOT, rather than a pure electrical disorder. (sources/scn5a-jaccep-2018, rating: high)
• SCN5A-BrS and conduction disease: BrS is frequently associated with electrical conduction defects at all cardiac levels. In SCN5A mutation carriers specifically, conduction intervals are prolonged throughout the heart — more so than in non-SCN5A BrS. Conduction disease (AVB, SSS) increases in prevalence and severity with age in SCN5A-BrS. (sources/scn5a-jaccep-2018)

ECG Patterns & Diagnosis

• ECG types:
  • Type 1 (coved) — diagnostic: J-point ≥2 mm, descending ST-segment, negative T-wave in V1/V2.
  • Type 2 (saddleback): J-point ≥2 mm, terminal ST ≥1 mm, positive or biphasic T — not diagnostic alone.
  • Type 3: saddleback, terminal ST <1 mm — not diagnostic alone. (sources/channelopathies-jaha-2025)
• High precordial lead positions (V1/V2 at ICS 2–4) increase diagnostic sensitivity ~1.5× versus standard positions; testing at both standard and high leads is required. (sources/brs-jaccep-2022)
• Shanghai Diagnostic Score (≥3.5 = probable/definite BrS; 2–3 = possible; <2 = non-diagnostic): integrates ECG type, clinical history (syncope, cardiac arrest), family history, and genetic findings. Accounts for phenocopies (RVOT compression, ischaemia, electrolyte disturbances, drug intoxication). (sources/channelopathies-jaha-2025, sources/brs-jaccep-2022)
• SCB provocation: Indicated for type 2/3 ECG or clinical/family history suspicion. Agents: ajmaline (most potent; mainly Europe), flecainide/pilsicainide (Europe/Japan), procainamide (least potent; North America). False-positive rate with high-dose ajmaline: ~8% in BrS families (Tadros et al.); ~27% of AVNRT patients and 4.5% of healthy controls (Hasdemir et al.) — standardisation of protocols needed. Drug-induced type 1 alone is insufficient for definitive diagnosis; no current consensus. (sources/brs-jaccep-2022)
• Echocardiogram in all patients to exclude structural heart disease; cardiac MRI in complex cases for RVOT delineation. (sources/brs-jaccep-2022)
• Genetic testing: Recommended (Class I per EHRA/HRS) when spontaneous type 1 ECG present — enables family screening. Only SCN5A testing is routinely performed. Testing for other genes only in consultation with a genetics expert when ≥2 family members are phenotypically affected and SCN5A is negative. SCN5A variant finding may contribute to future risk stratification alongside PRS from GWAS loci. (sources/arrhythmia-genetics-mgenetik-2025, sources/brs-jaccep-2022)
• Genetic testing is NOT indicated for isolated type 2 or type 3 Brugada ECG patterns alone — these patterns are not diagnostic for BrS and do not constitute an independent indication for genetic testing. Testing should be triggered by confirmed type 1 ECG or a clinical index of suspicion meeting diagnostic criteria. (sources/genetic-test-aha-2020 — high)
• Family screening: All first-degree relatives of BrS patients or unexplained SCD cases. Adults: standard + high-lead ECG ± SCB provocation; one-time screening is adequate if SCB-negative. Children: ECG at age 3, then every 3 years until age 15 (age-related phenotypic expression); avoid routine SCB before age 15 (higher adverse event risk in paediatrics). (sources/brs-jaccep-2022)

Risk Stratification

• Established high-risk markers:
  • Spontaneous type 1 ECG: 2–6× relative risk for SAE (resuscitated CA + SCD) across multiple large cohort studies.
  • Cardiogenic syncope: 2.5–5× relative risk. Non-cardiogenic syncope does not confer increased risk. (sources/brs-jaccep-2022)
• Quantified annual SAE rates: (sources/brs-jaccep-2022)
  • Cardiogenic syncope + spontaneous type 1 ECG: 2.3–3.7%/year
  • Cardiogenic syncope + drug-induced type 1: 0.98–1.96%/year
  • Asymptomatic + spontaneous type 1 ECG: 0.8–1.2%/year
  • Asymptomatic + drug-induced type 1: 0.21–0.3%/year
• "Brugada burden" concept: Spatial burden (type 1 ECG changes in peripheral leads beyond right precordial) and temporal burden (higher proportion of spontaneous type 1 ECGs during follow-up; greater ST-segment burden on 24-hour Holter) both independently predict SAEs. (sources/brs-jaccep-2022)
• Age and sex: Not independent risk markers in multivariate analysis after adjusting for spontaneous ECG and syncope. Patients ≥55 years at diagnosis have SAE rates comparable to the general population. (sources/brs-jaccep-2022)
• Family history of SCD: Not consistently predictive in large cohort studies; early familial SCD (first-degree relative <35 years) may confer risk (Sieira et al.). (sources/brs-jaccep-2022)
• Additional ECG markers (not yet validated in large adjusted studies): Fragmented QRS (f-QRS), QRS duration, S-wave duration, rJ interval, early repolarization pattern, Tpeak-end duration, QTc, signal-averaged ECG, and atrial fibrillation (independent predictor of SAE per Calò et al.). (sources/brs-jaccep-2022)
• Programmed ventricular stimulation (PVS): FINGER (n=1,029) and PRELUDE (n=308) registries failed to show predictive utility. Pooled analysis (Sroubek et al., n=1,312) found OR 2.7 but with low positive predictive value. A more recent pooled analysis provides evidence for a small predictive role of a non-aggressive stimulation protocol limited to double extrastimuli from the right ventricular apex only — not triple extrastimuli or multiple sites. Recommended only as a "tie-breaker" in selected intermediate-risk cases; not for routine use. (sources/brs-jaccep-2022, sources/scn5a-jaccep-2018)
• Risk stratification scores: Sieira score does not adequately stratify intermediate-risk patients (Probst et al.). Honarbakhsh model requires external validation. (sources/brs-jaccep-2022)

Management

Conservative

• All BrS patients: avoid Brugada-aggravating drugs (brugadadrugs.org), cocaine, cannabis, and excessive alcohol. (sources/VA-SCD-ESC-2022)
• Prompt antipyretic treatment during any febrile illness — fever unmasks the BrS phenotype and precipitates SAEs, especially in children. (sources/brs-jaccep-2022)
• Correct acute metabolic disturbances (hypokalemia, hyperkalemia, metabolic acidosis). (sources/brs-jaccep-2022)

Pharmacologic

• Quinidine: Inhibits Ito (primary antiarrhythmic mechanism in BrS), ICaL, and INa → prolongs effective refractory period. Reduces VF inducibility at PVS in ~90% (Belhassen series, n=60). Indications: recurrent ICD shocks, ICD-declined or ICD-contraindicated patients, atrial fibrillation co-management. Low-dose (≤600 mg/d) improves tolerability; side-effect-driven cessation in ~1/3 of patients; regular blood count monitoring required. (sources/channelopathies-jaha-2025, sources/brs-jaccep-2022)
• QUIDAM trial (hydroquinidine vs. placebo): Underpowered; did not demonstrate benefit. However, zero SAEs occurred in the hydroquinidine arm — clinical use is driven by observational and mechanistic data, not RCT evidence. (sources/brs-jaccep-2022)
• Isoproterenol (IV): For acute electrical storm/VF — potentiates ICaL to counteract arrhythmia. Recommended for short-coupled PVC-triggered VF. (sources/brs-jaccep-2022)
• Phosphodiesterase III inhibitors (cilostazol, milrinone): Alternative to isoproterenol via ICaL potentiation. (sources/brs-jaccep-2022)

Device Therapy

• Secondary prevention ICD: Indicated for all patients with resuscitated cardiac arrest (Class I). (sources/VA-SCD-ESC-2022)
• Primary prevention ICD: Recommended for BrS (spontaneous or provoked type 1) + cardiogenic syncope. (sources/brs-jaccep-2022)
• Asymptomatic, spontaneous type 1 ECG: Close follow-up; avoid primary prevention ICD unless additional high-risk features present (expert shared decision-making). (sources/brs-jaccep-2022)
• Asymptomatic with uncertain syncope + spontaneous type 1 ECG: Implanted loop recorder (ILR) may be considered. (sources/VA-SCD-ESC-2022)
• ICD complication burden: Annual rate — 3.3% inappropriate shocks + 4.5% other complications (lead malfunction, infection, psychological consequences) — meta-analysis n=1,539. SCD incidence without ICD ~0.19%/year vs. ~0.10%/year with ICD (Probst et al., n=1,613). (sources/brs-jaccep-2022)
• Subcutaneous vs. transvenous ICD:
  • ~15% of BrS patients fail initial S-ICD sensing screening.
  • S-ICD preferred in young patients without pacing requirement (mitigates intravascular infection risk).
  • Transvenous dual-chamber preferred when sinus node dysfunction or atrial arrhythmia discrimination is needed. (sources/brs-jaccep-2022)

Catheter Ablation

• Combined epicardial + endocardial approach: epicardial substrate modification in anterior RVOT + endocardial elimination of triggering PVCs. SCB provocation during procedure unmasks additional substrate. Proposed endpoint: resolution of J-point elevation despite pharmacologic provocation. (sources/brs-jaccep-2022)
• Pappone series (n=135): Acute ECG normalization in 100%; maintained in 133/135 (98.5%) at median 10-month follow-up. (sources/brs-jaccep-2022)
• Indicated for: recurrent ICD shocks not managed with medical therapy; ICD-declined or ICD-contraindicated patients. Insufficient data to support ablation in asymptomatic patients. (sources/VA-SCD-ESC-2022, sources/brs-jaccep-2022)

Drug-Induced Brugada Syndrome

• Drug-induced Brugada syndrome is defined as a normal pretreatment ECG that develops a type 1 Brugada pattern after drug exposure; the genetic substrate (SCN5A or other) may be present but previously silent. (sources/drug-arrhythmia-aha-2020, rating: very high)
• Culprit drugs (all via INa blockade unless noted): Antiarrhythmics — ajmaline (39–48.2% type 1 induction in high-pretest population), pilsicainide, flecainide, procainamide, propafenone; TCAs — amitriptyline, desipramine, imipramine, nortriptyline (2.3–15.3% in overdose settings); Anaesthetics — bupivacaine, procaine, propofol; Others — alcohol (ICa,L blockade), cocaine, lithium, loxapine, oxcarbazepine, trifluoperazine. Full up-to-date list: http://brugadadrugs.org. (sources/drug-arrhythmia-aha-2020)
• Drug-induced BrS is often asymptomatic; VT/VF onset can occur weeks to years after drug initiation; fever precipitates arrhythmias. SCD risk from drug-induced BrS is approximately 0.08%/year — substantially lower than spontaneous Brugada syndrome (~0.8–1.2%/year asymptomatic spontaneous type 1). (sources/drug-arrhythmia-aha-2020)
• Many patients with drug-induced type 1 ECG also exhibit spontaneous type 1 pattern on ambulatory monitoring — ambulatory ECG monitoring is required after drug discontinuation to exclude latent BrS. (sources/drug-arrhythmia-aha-2020)
• Management: Discontinue offending agent; screen for latent BrS with ambulatory monitoring; cardioversion/defibrillation or amiodarone for VT/VF; procainamide is contraindicated (potentiates INa inhibition); ICD if prior cardiac arrest, sustained VT, or syncope with spontaneous type 1 ECG; asymptomatic drug-induced BrS — observe without intervention other than avoidance of provoking agents. (sources/drug-arrhythmia-aha-2020)

AHA/ACC 2025 Sports Statement — BrS-Specific Guidance

• No data support competitive sports restrictions for BrS. Competitive sports participation is reasonable after expert assessment and management. (sources/competitive-sports-aha-2025, rating: very high)
• Athletes with BrS should avoid known arrhythmic triggers during sport: heat exhaustion, exercise during febrile illness, significant dehydration. Hydration during exercise must be prioritized. (sources/competitive-sports-aha-2025)
• This aligns with the known BrS arrhythmia physiology — arrhythmias occur predominantly at rest/sleep/after large meals (high vagal tone), not during exercise (high sympathetic tone). Exercise-triggered events are not a characteristic BrS feature.
• Prompt antipyretic treatment during any illness remains essential. (sources/competitive-sports-aha-2025)
• See concepts/Sports-Cardiology-SDM for full SDM framework.

ESC 2022 Guideline Recommendations

• Diagnose BrS with spontaneous type 1 ECG + no structural disease: Class I. Diagnose if SCA survivor with VF/PVT + type 1 pattern induced by SCB or fever: Class I. (sources/VA-SCD-ESC-2022)
• SCN5A genetic testing for probands: Class I. (sources/VA-SCD-ESC-2022)
• Avoid BrS-aggravating drugs, fever, cocaine, cannabis, excess alcohol: Class I. (sources/VA-SCD-ESC-2022)
• ICD for aborted CA or documented sustained VT: Class I. (sources/VA-SCD-ESC-2022)
• ILR for BrS + unexplained syncope: Class IIa. (sources/VA-SCD-ESC-2022)
• Catheter ablation of triggering PVCs/RVOT epicardial substrate for recurrent ICD shocks refractory to drug therapy: Class IIa (upgraded from IIb). (sources/VA-SCD-ESC-2022)
• PES may be considered in asymptomatic patients with spontaneous type 1 BrS ECG: Class IIb. (sources/VA-SCD-ESC-2022)
• Sodium channel blocker test if prior type 1 pattern already documented: NOT recommended (Class III). (sources/VA-SCD-ESC-2022)
• Catheter ablation in asymptomatic BrS patients: NOT recommended (Class III). (sources/VA-SCD-ESC-2022)

Emerging Therapies

• BrAID trial (NCT04641585): ML + transcriptomics platform for type 1 BrS diagnosis under investigation. (sources/channelopathies-jaha-2025)
• MOG1 overexpression: AAV9-mediated MOG1 (Nav1.5 chaperone/Ran guanine nucleotide release factor) delivery enhanced Nav1.5 cell-surface trafficking and reversed arrhythmic phenotype in SCN5A-G1746R knock-in mice — a pathway-targeted workaround to the SCN5A size constraint (~6,048 bp exceeds standard AAV ~4.7 kb packaging capacity). (sources/gene-therapy-arrhythmia-2025)
• ARumenamide-787: Inhibits Ito and enhances INa; showed promising anti-arrhythmic effects in canine BrS/ERS models. (sources/channelopathies-jaha-2025)
• RNA-based and noncoding RNA therapeutics are under preclinical investigation. (sources/channelopathies-jaha-2025)

Contradictions / Open Questions

• Unresolved pathophysiology: Three non-mutually exclusive mechanistic hypotheses (depolarization, repolarization, neural crest) remain unreconciled — this directly affects the rationale for ablation (targeting depolarization substrate) versus drug therapy (targeting repolarization/Ito). Any guideline recommendation for ablation implicitly assumes the depolarization/conduction hypothesis without fully resolving the debate. (sources/channelopathies-jaha-2025, sources/brs-jaccep-2022)
• Polygenic vs. monogenic architecture: GWAS data suggest common SNPs (not SCN5A alone) explain the majority of BrS cases; penetrance in SCN5A-positive families is only ~50%; family members without the variant may still have clinical BrS. Routine family screening cannot rely on genetic testing alone. (sources/brs-jaccep-2022)
• BrS PRS predicts ECG phenotype, not arrhythmic events — critical clinical gap: The Ishikawa 2024 BrS PRS (OR 2.12/SD) is validated for predicting spontaneous type 1 ECG and positive SCB provocation — but not for predicting VF or SCD. This means PRS can identify individuals with a polygenic electrophysiological susceptibility without distinguishing which of those individuals face actual arrhythmic risk. The GWAS architecture explains why ~80% of BrS is "genotype-negative" but does not resolve the question of who needs an ICD. (sources/gwas-arrhythmias-cmp-genes-2025, rating: high)
• SCN5A testing yield: SCN5A is causative in only 20–30% of BrS probands — a Class I testing recommendation yields a positive result in the minority, and a negative result does not exclude the diagnosis. (sources/channelopathies-jaha-2025, sources/VA-SCD-ESC-2022, sources/arrhythmia-genetics-mgenetik-2025)
• PVS role: FINGER and PRELUDE registries failed to show predictive utility for PVS, yet it is still ESC Class IIb and considered useful as a "tie-breaker" in intermediate-risk cases. The need to evaluate PVS jointly with all noninvasive ECG risk markers simultaneously has not been addressed in a large prospective study. (sources/VA-SCD-ESC-2022, sources/brs-jaccep-2022)
• Catheter ablation asymmetry: ESC 2022 upgraded ablation for recurrent ICD shocks to Class IIa, yet ablation in asymptomatic BrS is simultaneously Class III. This sharp binary may not reflect the clinical reality of intermediate-risk patients — e.g., spontaneous type 1 ECG + family history of SCD but no personal arrhythmic event. (sources/VA-SCD-ESC-2022)
• ICD overuse in asymptomatic BrS: Annual SCD rate in asymptomatic BrS without ICD (~0.19%) is lower than the combined annual ICD complication rate (inappropriate shocks 3.3% + other complications 4.5%), raising concern that primary prevention ICD in asymptomatic patients without additional high-risk features may cause net harm. (sources/brs-jaccep-2022)
• QUIDAM trial gap: The only RCT for hydroquinidine in BrS was underpowered and did not demonstrate benefit over placebo. Quinidine/hydroquinidine remains the standard pharmacologic recommendation driven entirely by observational and mechanistic data. (sources/brs-jaccep-2022)
• ClinGen refutes/disputes the vast majority of published BrS genes (2026): Of the ~20+ genes historically attributed to BrS, ClinGen experts have reclassified nearly all non-SCN5A BrS genes as "Disputing" or "Refuting" as of 2026. Notably: TRPM4 and SCN3B are refuting (12/2025); KCNH2, CACNA1C, ABCC9, CACNB2, SCN10A are disputing (2025). This has direct implications for genetic panels — positive results in these genes in a BrS patient should not be attributed as causative without corroborating evidence. The oligogenic/polygenic model of BrS (21 GWAS loci) provides the mechanistic explanation. (sources/clingen-summary-2026-05-09, rating: high)

SCB Provocation Testing — 2025 EHRA Consensus Guidance

Indications (>90% consensus)

• Unexplained VF/polymorphic VT after comprehensive workup (ECG, echo, coronary assessment, cardiac MRI)
• Asymptomatic first-degree relative of definite SCN5A-negative BrS patient
• Type 2/3 Brugada ECG pattern + cardiac/suspected cardiac syncope without significant structural disease
• First-degree relative of SADS decedent when death circumstances are suggestive of BrS (sleep/fever/suspicious ECG)
• SCN5A variant of uncertain significance + symptoms/family history (segregation analysis)
• Substrate ablation procedure for symptomatic BrS — to enable substrate mapping; only circumstance where SCB is used with documented type 1 pattern (sources/pharmacological-provocation-europace-2025 — high)

Contraindications (>90% consensus)

• Documented type 1 Brugada pattern already present (except phenocopy or ablation)
• Asymptomatic incidental type 2/3 ECG with no additional supporting features
• Patients with SCN5A P/LP variants — increased ventricular arrhythmia risk during SCB testing; test only in expert centre for specific indications (VUS assessment, complex overlap)
• Active fever (sources/pharmacological-provocation-europace-2025 — high)

Preferred Agent and Protocol

• Ajmaline preferred when available: class 1A, t½ ~5 min, max 1 mg/kg or 100 mg over 5–10 min
• High precordial lead positions (V1/V2 at ICS 2–4) required; continuous or at minimum every 30–60 s ECG
• Isoproterenol must be available for ventricular arrhythmia management
• Higher-risk patients (pre-existing AV conduction disturbances, SCN5A variants): test in cardiac catheter laboratory with temporary pacing (sources/pharmacological-provocation-europace-2025 — high)

Key Contextual Point — Polygenic Basis

• Common polygenic variants (PRS from GWAS loci) independently predict positive ajmaline response; family members without SCN5A variants may test positive due to polygenic susceptibility
• Drug-induced type 1 pattern without other supportive evidence may represent polygenic heritability, not monogenic BrS — clinical implications for the family are uncertain (sources/pharmacological-provocation-europace-2025 — high)

Connections

• Related to concepts/Drug-Induced-Arrhythmia
• Related to concepts/Cardiac-Action-Potential
• Related to concepts/Electrical-Remodeling
• Related to sources/membrane-potential-physrev-2021
• Related to concepts/Ion-Channel-Mutations
• Related to concepts/Shanghai-Score-System
• Related to concepts/Sudden-Cardiac-Death
• Related to concepts/Electrical-Storm
• Related to concepts/iPSC-Derived-Cardiomyocytes
• Related to concepts/Cardiogenetic-Centers
• Related to concepts/Variant-Reclassification
• Related to concepts/Pharmacological-Provocation-Testing
• Related to entities/SCN5A
• Related to entities/Early-Repolarization-Syndrome
• Related to concepts/Sports-Cardiology-SDM
• Related to concepts/GWAS-Cardiac-Genetics
• Related to concepts/Polygenic-Risk-Score
• Related to concepts/Epigenetics-Cardiac-Arrhythmia

Sources

• Related to sources/competitive-sports-aha-2025
• Related to sources/genetic-test-aha-2020
• Related to sources/pharmacological-provocation-europace-2025
• Related to sources/scn5a-jaccep-2018
• Related to sources/gwas-arrhythmias-cmp-genes-2025
• Related to concepts/ClinGen-Gene-Disease-Validity
• Related to sources/clingen-summary-2026-05-09
• Related to sources/genetics-va-fcvm-2022