Brugada Syndrome

Arrhythmogenic channelopathy with right precordial ST-segment elevation, ventricular fibrillation and sudden death risk in a heart without macroscopic structural disease; SCN5A is the only gene with a definitive association.

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

In 1992, Pedro and Josep Brugada published in the Journal of the American College of Cardiology eight patients, six men and two women, with recurrent episodes of aborted sudden death that did not fit known diseases. The sinus rhythm ECG showed a right bundle branch block pattern, a normal QT interval and persistent ST-segment elevation from V1 to V2–V3, unexplained by ischaemia, electrolyte disturbances or structural heart disease; ventricular biopsies in four showed no histological abnormalities, the arrhythmia was rapid polymorphic ventricular tachycardia initiated by a short-coupled premature beat, programmed stimulation reproduced it in four of seven studied patients, and four had a prolonged HV interval. One patient receiving amiodarone died suddenly during pacemaker implantation; all four with an implantable cardioverter-defibrillator (ICD) were alive at follow-up completion [20].

In 1996, Japanese cardiologists proposed the eponym “Brugada syndrome”. The following year, the entity was recognised as equivalent to sudden unexpected nocturnal death syndrome in Southeast Asia: bangungut in the Philippines, lai tai in Thailand, pokkuri in Japan, dolyeonsa in Korea, dream disease in Hawaii and “sudden male death syndrome” in China, terms referring to nocturnal deaths of apparently healthy young men without an explanatory autopsy lesion [1]. GeneReviews adds non-lai tai in Laos and records the same SCN5A variant in Brugada and SUNDS patients, supporting phenotypic, genetic and functional unification [2].

The genetic basis was demonstrated in 1998 by Chen and colleagues, who identified a missense, a donor splice-site and a frameshift SCN5A variant in three families with idiopathic VF; the missense channel recovered from inactivation faster than normal and the truncated channel was non-functional [21]. Subsequent decades brought three conceptual changes. First, diagnosis: the 2013 criterion accepting a drug-induced type 1 pattern as diagnostic increased overdiagnosis and prompted the 2016 Shanghai score, which considers only spontaneous type 1 diagnostic on its own [6]. Second, genetics: ClinGen's 2018 re-evaluation retained definitive evidence only for SCN5A, classifying the other 20 commercially tested genes as disputed, while genome-wide association studies demonstrated a polygenic component [7, 22]. Third, treatment: epicardial right ventricular outflow tract substrate ablation progressed from case reports to multicentre registries and two randomised trials published in 2025 [23–25].

Current management rests on the 2022 European Society of Cardiology (ESC) guidelines for ventricular arrhythmias and the prevention of sudden cardiac death, on the 2026 international consensus organised by the Asia Pacific Heart Rhythm Society (APHRS), which updates the 2016 consensus on J-wave syndromes and modifies the ESC algorithms, on the 2025 European Heart Rhythm Association (EHRA) consensus on pharmacological provocation testing and on the 2022 consensus on genetic testing in cardiology [4, 6, 17, 18]. Long QT syndrome, catecholaminergic polymorphic ventricular tachycardia and the other channelopathies are addressed as differential diagnoses and as phenotypes of allelic overlap.

2. Molecular Genetics and Pathophysiology

2.1. Nav1.5 and the action potential

SCN5A, at 3p22.2, encodes the voltage-gated cardiac sodium channel alpha subunit Nav1.5, responsible for sodium current (I_Na) during action potential phase 0 and thus conduction velocity in the atria, His–Purkinje system and ventricles [1, 2]. In Brugada syndrome, SCN5A disease variants reduce sodium current availability through altered channel structure, function or membrane trafficking; this is loss of function, unlike long QT syndrome type 3, caused by gain of function with persistent late sodium current [2, 26]. ClinGen classifies SCN5A as having sufficient haploinsufficiency evidence (June 2021 dosage curation), consistent with truncating variants as a disease mechanism [8].

2.2. Repolarisation and depolarisation hypotheses

Two pathophysiological models have been proposed. The repolarisation hypothesis attributes ECG patterns and arrhythmia to an action potential phase 1 imbalance between inward currents (I_Na and L-type calcium current) and transient outward potassium current (I_to), denser in right ventricular epicardium: loss of the epicardial action potential dome creates a transmural gradient and repolarisation heterogeneity favouring phase 2 re-entry [1, 6]. The depolarisation hypothesis attributes them to conduction delay and block in right ventricular outflow tract epicardium, the latest activated region: compromised tissue fails to become excited, and the electrotonic injury current generates ST elevation and reduced T-wave depth in right precordial leads [6].

The 2026 consensus considers both mechanisms complementary and describes Brugada as a microstructural–electrical continuum. Autopsy studies of relatives showed greater epicardial collagen and reduced connexin 43 signal in the right ventricular outflow tract; a larger series identified interstitial and focal replacement fibrosis throughout the heart, predominantly in the outflow tract and epicardium, irrespective of an SCN5A variant. Fibrosis creates a branching myocardial network with source–sink mismatch and block at branching points; reduced I_Na lowers conduction reserve, while sodium channel blockers increase block, underpinning provocation testing [6]. Clinical Cardiogenetics notes that structural changes remain of uncertain relevance, that the current definition excludes structural abnormality, and that PKP2 variants described in Brugada patients have not been confirmed as causal [1].

Carriers of P/LP SCN5A variants have more extensive epicardial substrates, with microstructural fibrosis in both ventricles; in 200 high-risk probands undergoing epicardial mapping, an SCN5A variant explained more than 26% of substrate area variation and was associated with spontaneous type 1 and more frequent aborted cardiac arrest or spontaneous VT/VF [6, 27]. An autoimmune mechanism has been proposed: anti-Nav1.5 autoantibodies reducing I_Na were described in approximately 90% irrespective of genotype, but the consensus regards validation as a research priority rather than a clinical biomarker [6].

2.3. Genetic architecture

GeneReviews, reviewed in 2022, lists SCN5A and 42 additional genes and attributes approximately 65% of cases to an unknown cause; SCN5A sequencing detects 99% of known pathogenic variants, and deletion/duplication analysis approximately 1% [2]. In 2020, Clinical Cardiogenetics presented estimated gene contributions below 30% for SCN5A, below 5% for CACNA1C and below 1–2% for others, stating that comprehensive analysis identified the cause in approximately 35% [1]. These proportions predated systematic validity re-evaluation and included variants now classified as uncertain under American College of Medical Genetics and Genomics (ACMG) criteria; they should not be used as current diagnostic yield.

2.4. Gene–disease validity (ClinGen)

In 2018, three curation teams assessed 21 clinically tested genes: only SCN5A had definitive evidence; the other 20 were initially classified as limited and, after clinical expert panel review, disputed [7]. Inherited cardiovascular disease panel recurations between 2025 and January 2026 retained disputed status for CACNA1C (February 2025), KCNH2 (June 2025), KCNE3 (July 2025), SCN10A (September 2025), ABCC9 (October 2025), KCNJ8 (December 2025), FGF12 and TMEM168 (January 2026), and classified RANGRF (October 2025), SCN3B and TRPM4 (December 2025) and SLMAP (January 2026) as refuted; GPD1L, SCN1B, SCN2B, CACNA2D1, HCN4, KCND3, KCNE5, PKP2 and ANK2 retain their 2017 disputed classification. In October 2025, ClinGen grouped SCN5A arrhythmic phenotypes under “SCN5A-related cardiac rhythm disorder”, with definitive validity; dilated cardiomyopathy 1E was classified definitive in March 2026 [8]. The 2025 CACNB2 recuration noted only three scoreable probands; for SCN10A, most of the 20 reported variants were too frequent in gnomAD to cause dominant disease and the gene has very low cardiac expression [8]. The 2026 consensus concludes that SCN5A remains the only definitively associated gene [6].

2.5. SCN5A variants, nomenclature and correlations

Historical literature numbers Nav1.5 on the 2016-amino-acid isoform (NM_198056, numbering equivalent to NM_001099404.2), including glutamine 1077; MANE Select NM_000335.5 encodes the 2015-amino-acid isoform without that glutamine, so residues downstream of 1077 decrease by one [5]. The following correspondences were confirmed using VariantValidator and ClinVar rather than calculated manually [30, 31].

Variant type influences severity. Carriers of truncating or missense variants reducing I_Na by more than 90% have more syncope and conduction disturbances than those with variants reducing current by 90% or less; non-missense variants and missense variants in transmembrane segments or the pore are associated with greater arrhythmia risk during pharmacological testing [1]. In the Japanese registry, carriers of variants with patch-clamp-demonstrated loss of function (n = 45) had lethal arrhythmic events at 7.9% annually, versus 5.1% in carriers classified only by in silico algorithms and 2.5% in all probands; the 15 carriers without loss of function had no events [33]. In 2026, automated patch clamp of 252 missense and in-frame variants from a cohort of 3335 patients reclassified 110 of 225 VUSs (104 to likely pathogenic and 6 to likely benign); severe loss-of-function variants (Z ≤ −6) had estimated penetrance of 24.5% (CI 15.9–37.7%) and an odds ratio of 501 for Brugada syndrome [34].

2.6. Modifiers and allelic disorders

Incomplete penetrance and variable expressivity prompted modifier searches: p.(His558Arg); a six-polymorphism SCN5A promoter haplotype associated with reduced expression in Japanese populations; SCN10A and transcription factor HEY2, identified as SCN5A expression modifiers; and double variants associated with more severe phenotypes. A low SCN5A copy-number variant rate, changes in expression-regulating GATA4 and GATA5 transcription factors, and absence of a specific mitochondrial variant were described [1]. Loss-of-function SCN5A variants also cause progressive conduction disease (Lenègre disease), sinus node dysfunction, dilated cardiomyopathy, atrial fibrillation and familial VF; the same variant commonly causes Brugada and conduction disease in the same patient or family [2, 26]. A 2026 study of 162 P/LP SCN5A carriers from 43 families showed negative sodium blocker tests in 43%; among these, 36% had intraventricular conduction disturbance and 28% first-degree AV block, 52% developed progressively slower conduction, and arrhythmic prognosis was favourable [35].

3. Clinical Spectrum and Manifestations by System

3.1. Presentation and natural history

Presentation ranges from asymptomatic carriage to sudden death, with syncope, seizures and nocturnal agonal breathing caused by polymorphic VT or VF; sudden death may be the first manifestation, reported in approximately 5% in a study cited by Clinical Cardiogenetics [1]. Arrhythmias usually occur during sleep or rest with bradycardia and vagal tone; fever is a frequent precipitant [1]. In a multicentre registry of 154 patients with documented ventricular tachyarrhythmia onset, 80.5% had polymorphic VT, 16.9% monomorphic VT and 2.6% both; approximately one-quarter of polymorphic and one-third of monomorphic episodes had pause-dependent onset [36].

SABRUS collected 678 patients from 23 centres in 10 Western and 4 Asian countries with a first documented arrhythmic event: 94.2% were aged 16–70 years, 4.3% younger than 16 and 1.5% older than 70; the peak occurred at 38–48 (mean 41.9 ± 14.8 years); adult women had first events 6.5 years later than men, and White and Asian patients had the same median age (43 years) [10]. In the same survey, 35 of 588 patients (6%) had events during febrile illness; the proportion was highest in children, with 65% febrile among events at ages 0–5; women with febrile events were children or elderly, and no febrile events occurred in Asians younger than 24 [37].

The 2021 French national protocol (PNDS) of the Haute Autorité de Santé (HAS) places the mean age at sudden death at 41 ± 15 years and describes the usual circumstances of discovery: in most cases, an ECG performed for another reason (preoperative assessment, insurance or occupational health examination) or during family screening, often recorded by a general practitioner or an anaesthetist; more rarely, syncope; and, less frequently still, cardiac arrest, although according to the same document the syndrome accounts for about one third of cardiac arrests in a structurally normal heart. Reflex syncope is frequent in these patients and ventricular arrhythmias also tend to occur during periods of vagal predominance, which makes clinical distinction difficult; about half of syncopal episodes occur at night, and atypical forms should be actively sought: abrupt nocturnal awakening, abnormal movements during sleep and occasional nocturnal enuresis. Left ventricular function does not deteriorate over time and there is no progression to heart failure; arrhythmic risk decreases over life and is lower after 60 years of age, and the frequency of the pattern appears to decrease after 65 years, particularly in men [9].

3.2. Sex, hormones and age

Men are more symptomatic (approximately 3:1 in Clinical Cardiogenetics), but male predominance is absent before 16, when testosterone levels are similar in both sexes [1]. The 2026 consensus gives male:female ratios of 9:1 in Asians and 7:3 in Caucasians, annual female event rates of 0.25–0.7%, and male VF hazard ratios (HRs) of 2.9–4.5; before puberty, girls are more often symptomatic. Female risk factors resemble male factors: being a proband (HR 10.2), previous cardiac arrest (HR 25.4–69.4), syncope (HR 6.8), spontaneous type 1 (HR 2.7), sinus node dysfunction (HR 9.1), fragmented QRS (HR 20.2), QRS >120 ms (HR 4.7) and induced VF (HR 5.3) [6].

3.3. Associated cardiac manifestations

3.4. Paediatric and elderly populations

Large studies of asymptomatic children found the Brugada pattern in 0.01–0.02%, suggesting age-related clinical expression; fever is the main precipitant, and risk is greater in previously symptomatic children with spontaneous type 1 [1]. SCN5A carrier proportions are higher in paediatric probands (47–67%) than adults [28]. Elderly data are sparse: an analysis cited by Clinical Cardiogenetics described fewer ventricular arrhythmias and less family sudden death history than in younger patients, and a Taiwanese study above age 55 found Brugada pattern prevalence above the global mean without different overall or cardiac mortality [1]. The 2026 consensus cites VF rates of 0.3% annually above 60 and notes that rare VF in older people does not obviate secondary prevention [6].

4. Clinical Recognition and Warning Signs

Recognition rests on clinical events and ECG clues. Arrhythmic syncope starts abruptly without prodrome, occurs supine, during sleep or at night, may accompany nocturnal agonal breathing, seizures or urinary incontinence, and has an annual VF rate of approximately 5.5% when strongly suspected; conversely, blurred vision, nausea, vomiting, pallor, light-headedness (relative risk 0.4) and sweating suggest reflex syncope, whose prognosis approaches asymptomatic patients' [6]. A minority of episodes result from bradyarrhythmia [6].

ECG risk markers assembled by the 2026 consensus include spontaneous type 1 (VF HR 1.8–6.6), spontaneous changes in type and ST level, prolonged PR (170 or 200 ms cut-offs), wide QRS (>90, >105 or >120 ms, study-dependent), fragmented QRS (HR 4.1–5.2 overall; 5.9–7.4 in asymptomatic patients; low-pass filter ≥100 Hz for detection), aVR sign (R ≥0.3 mV or R/q ≥0.75), significant lead I S wave, type 1 in limb leads (9–10%; OR 4.6), inferolateral early repolarisation, Tpeak–Tend ≥95–100 ms, signal-averaged ECG late potentials and accentuated ST during early exercise recovery (37%; HR 3.17) [6]. Most derive from observational studies with discordant results and lack sufficient independent validation to indicate an ICD alone.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Electrocardiographic patterns

The second consensus report (2005) described three patterns: type 1, coved ST elevation above 2 mm followed by a negative T wave in at least one right precordial lead, the only diagnostic pattern; and saddleback types 2 and 3, with ST elevation of 2 mm or below 2 mm, suggestive but not diagnostic [1]. The 2012 consensus reduced these to two descriptive patterns: type 1 and type 2 (saddleback, ST elevation ≥0.5 mm, usually ≥2 mm in V2, an r' wave with a slow downstroke and positive V2 T wave) [1]. GeneReviews retains three types [2]. Criteria based on the r' triangle were proposed to distinguish type 2 from benign incomplete right bundle branch block: β angle ≥58° (positive predictive value 73%, negative 87% for type 1 conversion), triangle base 5 mm below the apex ≥4 mm (specificity 96%, sensitivity 85%), and baseline width at the isoelectric line >1.5 mm [1]; the 2025 EHRA consensus gives cut-offs of α >50° (sensitivity 71%, specificity 79%), β >58° (79% and 83%), base at 5 mm >140 ms or >3.5 mm (81% and 82%), and isoelectric baseline width >60 ms or >1.5 mm (95% and 78%) [4].

Recording V1 and V2 in the second and third intercostal spaces increases sensitivity because the anatomical relationship between the right ventricular outflow tract and standard leads varies; spontaneous type 1 in high leads has a similar prognosis to the standard position [1]. Measurement should use the isoelectric line (PQ and TP segments) and locate the J point, the QRS end, in a limb or lateral lead; at least two beats must meet criteria, with ST continuously descending without concavity or a horizontal portion to the negative T wave [4]. The pattern is dynamic: prolonged 12-lead Holter monitoring revealed intermittent spontaneous type 1 in approximately 30% previously classified as drug-induced only in Clinical Cardiogenetics, and 13–34% in EHRA [1, 4].

5.2. Diagnostic criteria

GeneReviews establishes clinical diagnosis with type 1 in more than one right precordial lead, with or without a sodium blocker, without another explanatory factor, plus at least one of: documented VF, self-terminating polymorphic VT, familial sudden death, a coved pattern in relatives, electrophysiological inducibility, syncope or nocturnal agonal breathing; approximately 75% of diagnoses rest on clinical history and ECG [2]. ESC 2022 (Recommendation Table 43, read in full text) recommends diagnosis without other heart disease with spontaneous type 1 (class I, level C), and in VF or polymorphic VT cardiac arrest survivors with sodium blocker- or fever-induced type 1 (I, C); with induced type 1 and no other heart disease, diagnosis should be considered with at least one of three features—arrhythmic syncope or nocturnal agonal breathing, familial Brugada, or sudden death before 45 in a relative with negative autopsy and suspicious circumstances (IIa, C)—and may be considered with an isolated induced pattern (IIb, C). Sodium blocker testing is not recommended after a previous type 1 pattern (III, C) [17]. The guideline justifies additional clinical criteria because provocation specificity is limited, with 2–4% prevalence in healthy individuals [17]. AHA/ACC/HRS 2017 considers sodium blocker provocation useful in suspected Brugada without spontaneous type 1 (IIa, B-NR) and recommends observation without therapy in asymptomatic drug-induced-only type 1 (I, B-NR) [16]. The Shanghai score, largely adopted by ESC and modified in the 2026 consensus, quantifies this reasoning [6, 28]:

The table reproduces the modified 2026 consensus version, checked against the original publication XML, indicating the item present only in 2016 [6, 28]. Isolated drug-induced type 1 (2 points) plus a P/LP SCN5A variant (0.5) totals 2.5 and remains “possible” [18].

The 2021 French PNDS retains the definition of the 2013 consensus and of the 2015 ESC guidelines: convex elevation of the J point or of the ST segment greater than 0.2 mV (2 mm with the usual calibration of 10 mm/mV), encompassing the usually negative T wave, in at least one lead V1 or V2 placed in the 4th, 3rd or 2nd intercostal space, spontaneous or after an intravenous sodium channel blocker [9]. It therefore diverges from the 2022 ESC guidelines, which no longer accept an induced-only type 1 as an isolated diagnosis without additional clinical or family data [17]. The PNDS reproduces the Shanghai score in its 2016 version (with the item of atrial fibrillation or flutter before 30 years of age and the wording “likely pathogenic variant in a susceptibility gene”), assigns it the aim of limiting the diagnosis in people who have only the electrocardiographic pattern and thus the use of invasive techniques in low-risk patients, and stresses that the score has not been validated in independent cohorts; in the PNDS table, the threshold of the “non-diagnostic” category is printed as “2 points”, overlapping the “2 to 3 points” category, and should be read as less than 2, as in the original version [9, 28]. The same document insists on the distinction between a merely suggestive appearance (the former types 2 and 3), carrying no arrhythmic risk of its own, and the complete type 1 appearance, illustrated respectively in appendices 4 and 3, and recommends that, in case of diagnostic doubt, the ECG be reviewed by a reference or competence centre before the diagnosis is communicated to the patient [9].

5.3. Sodium channel blocker provocation testing

Testing unmasks type 1 with clinical suspicion but no spontaneous pattern. It should occur in hospital under an institutional protocol with trained staff, continuous 12-lead ECG or recordings every 30–60 seconds using high V1–V2, vital sign monitoring, advanced life support, a defibrillator and available isoproterenol; with first-degree AV block, conduction disturbances or an SCN5A variant, it should occur in a catheterisation laboratory with temporary pacing capability [4]. Ajmaline is preferred when available because of its short half-life and greater potency [4].

Source of the table: 2025 EHRA consensus [4]. None of these drugs carries provocation testing in its label. In the US label for injectable procainamide (antiarrhythmic indication), direct intravenous injection should not exceed 50 mg per minute (100 mg every 5 minutes up to 500 mg, with a 10-minute pause), or a loading infusion of 500–600 mg over 25–30 minutes is given, with a maximum of 1 g; the consensus bolus of up to 100 mg/min exceeds the label rate and lies outside the label conditions [39]. Oral flecainide has been used when no intravenous alternatives exist [1, 4]. In children, Clinical Cardiogenetics gives ajmaline 1 mg/kg or flecainide 2 mg/kg over 10 minutes, with the same weight protocol as in adults [1, 4]. The infusion is stopped when the maximum dose is reached, a type 1 appears, the QRS widens by more than 30% relative to baseline (some experienced centres accept up to 50%), ventricular arrhythmia beyond isolated extrasystoles occurs, profound bradycardia or sinus arrest, second-degree type II or third-degree AV block, or an allergic reaction [4]. Clinical Cardiogenetics expresses the same limit as QRS widening to more than 130% of the baseline value [1]. The ECG is recorded until the PR and QRS return to baseline; some centres observe for at least one hour after an uncomplicated ajmaline test [4]. The test should not be performed in patients with fever, second-degree type II or third-degree AV block, severe sinus node dysfunction or significant structural heart disease [4].

The French PNDS protocol differs from the EHRA consensus in several operational details. The test is usually performed as a day-hospital procedure, in a setting with immediate resuscitation capability, with the ECG continuously monitored by a trained operator; to record the 4th and 3rd intercostal spaces simultaneously, leads V5 and V6 are moved to the 3rd space, and a recording in the 2nd space is added if doubt persists. In adults and adolescents from 15 years of age, ajmaline (1 mg/kg, maximum 100 mg) or flecainide (2 mg/kg, maximum 150 mg) is administered intravenously by syringe driver over 10 minutes; the PNDS acknowledges that a 5-minute ajmaline infusion has been proposed, but prefers 10 minutes to reduce false positives. The PNDS gives only the dose per kilogram; the absolute maxima are those of the EHRA consensus, which cap the dose above 100 kg body weight for ajmaline and above 75 kg for flecainide [4, 9]. The injection is stopped as soon as type 1, a ventricular arrhythmia or rapid QRS widening appears; on the basis of the experience of the French centres, the PNDS considers the 30% QRS increase threshold too low, leading to premature interruption of too many tests, and prefers the dynamic criterion of rapid widening, whereas the EHRA consensus retains 30%, allowing up to 50% in experienced centres [4, 9]. With rapid QRS widening, the antidote is a sodium load, with molar sodium bicarbonate (8.4%, 1 mmol/mL) or molar sodium lactate; with ventricular arrhythmia, the heart rate is accelerated with isoprenaline [9]. The PNDS does not give the bicarbonate dose; the 2017 AHA/ACC/HRS guideline supports administration of sodium, as chloride or bicarbonate, in sodium channel blocker toxicity on the basis of limited animal data, without a dose [16]. By extrapolation from the US label for sodium bicarbonate injection, whose regimen for the acidosis of cardiac arrest in adults is 44.6 to 100 mEq as a rapid intravenous bolus, followed by 44.6 to 50 mEq every 5 to 10 minutes according to blood gases, with a risk of hypernatraemia because it is a hypertonic solution, the dose should be titrated to the QRS response; sodium channel blocker toxicity is not among the label indications [40]. Monitoring is extended for a few hours, until the ECG returns to baseline. The PNDS adds that the test is often falsely negative before 15 years of age and does not recommend it below that age, except in particular circumstances, whereas the EHRA consensus and the Dutch consensus use puberty as the reference point [4, 9, 28].

Source: PNDS HAS 2021 [9]. The two lists converge on the indications after unexplained cardiac arrest and in relatives of sudden death victims, but diverge on the isolated finding of type 2 or 3: the EHRA consensus advises against routine testing without other clinical, electrocardiographic or family data, whereas the PNDS admits it for discussion when the appearance is accentuated in the high leads [4, 9]. Before the test, the asymptomatic person should be informed that a positive result does not lead to specific treatment, only to the general preventive measures [9].

Test limitations are quantifiable. Approximately 25% may be false negatives, and negative flecainide testing in a sudden death survivor does not exclude disease [1]. In SCN5A carriers, ajmaline induces type 1 in 75–80% and flecainide in 77%; ajmaline sensitivity was 100% versus flecainide's 77% in obligate carriers, and only 68% (15/22) previously ajmaline-positive patients reproduced type 1 with flecainide [4]. False positives occur: induced type 1 in 16% with arrhythmogenic right ventricular cardiomyopathy, 18% with myotonic dystrophy, 27% with AV nodal re-entrant tachycardia, 16% with an accessory pathway and 4% of controls; 3% of 100 healthy Caucasian volunteers and 9% of a French general population group with suspicious ECGs had ajmaline type 1 [4]. Test arrhythmia ranges from 0% to 17.8% across Clinical Cardiogenetics series, more often with prolonged baseline conduction and SCN5A variants [1, 4]. A Canadian registry of 947 procainamide tests published in December 2025 found asymptomatic ventricular arrhythmia in 2 (0.2%); yields were 7.2% after unexplained cardiac arrest, 22.2% with familial Brugada, 46.6% with type 2/3 and 92% with intermittent spontaneous type 1 (implicit sensitivity 92%); none of 137 drug-induced type 1 patients without prior arrest met the composite arrhythmic endpoint over 5.9 ± 4.5 years [41]. The study does not directly compare procainamide and ajmaline within individuals, and absence of events over approximately six years does not mean zero lifetime risk.

Source: EHRA 2025 [4]. Prepubertal sensitivity is limited: approximately 30% of initially negative preadolescents became positive after puberty in Clinical Cardiogenetics, and 23% of 53 asymptomatic children in the Dutch consensus, which recommends fever ECGs and reserves prepubertal testing for exceptions such as unexplained arrest [1, 28]. The “full stomach” test exploiting postprandial vagal tone has been proposed as an alternative; adrenergic stimulation reduces and vagal stimulation increases ST elevation [1].

5.4. Genetic testing

Source: 2022 consensus [18]. ESC 2022 recommends SCN5A testing in Brugada probands (class I, level C), estimating yield at approximately 20%, with SCN5A the only clinically supported gene [17]; AHA/ACC/HRS 2017, before ClinGen re-evaluation, assigned counselling and testing in suspected or established syndrome class IIb (C-EO) to facilitate cascade screening, noting that genotype did not correlate with event risk in then-available studies [16]. Reports should identify gene, versioned transcript (NM_000335.5), HGVS c. and p. nomenclature, zygosity, ACMG/AMP classification and technical limitations (exon and intronic boundary coverage, deletion/duplication detection, no deep regulatory analysis such as RE5) [2, 29]. A P/LP variant confirms diagnosis in a type 1 proband, but a negative test does not exclude it because approximately 80% of European probands lack SCN5A variants [6, 18]. Sequencing's technical sensitivity for SCN5A variants (99%) should not be confused with syndrome clinical sensitivity, below one-third [2]. A VUS does not become pathogenic through partial segregation or drug response; calibrated functional data (automated patch clamp) may provide ACMG PS3/BS3 evidence [34]. A three-SNP polygenic score (rs11708996, rs10428132, rs9388451) below the tenth percentile had 99% sensitivity and 93% negative predictive value for induced type 1 in 1368 ajmaline-tested patients at one centre; the consensus requires validation elsewhere [18].

5.5. Evaluation after sudden death in the young

Complete autopsy is recommended for all sudden deaths at ages 1–40, identifying a cause in more than 70%; negative cases (up to approximately 30%) are termed sudden arrhythmic death syndrome (SADS) [38]. DNA material should be retained (EDTA blood, frozen cardiac muscle, liver or spleen, or skin biopsy if autopsy is declined); molecular autopsy yield ranges from 13% to 32%, approaching 40% combined with familial clinical assessment [38]. First-degree relatives, obligate carriers and symptomatic relatives should undergo history, examination, 12-lead ECG at rest, after rapid standing and with high right precordial leads, exercise testing and echocardiography; ajmaline testing, MRI, Holter and signal-averaged ECG form the second level [38]. A UK study assessing 57 families of SADS victims aged 4–64 identified inherited disease in 53% [38].

The 2022 French PNDS on sudden death in the young defines unexplained sudden death as the unexpected death without apparent cause of a person older than one year (before one year, the situation falls under sudden infant death, usually of different causes), occurring within the hour following the change in cardiovascular status when witnessed, or in a person seen alive and in good health in the previous 24 hours when unwitnessed. About 80% of out-of-hospital cardiac arrests are of cardiac origin; between 1 and 35 years of age potentially inherited heart diseases, channelopathies and cardiomyopathies predominate, and from 35 years coronary artery disease becomes the most frequent cause [19]. The circumstances guide the diagnosis: death of a young or middle-aged man during sleep or a febrile episode suggests Brugada syndrome; death during exertion suggests long QT syndrome, catecholaminergic polymorphic ventricular tachycardia or arrhythmogenic cardiomyopathy (genes such as LMNA, FLNC and DSP); a road traffic accident without apparent cause or the drowning of a good swimmer may correspond to sudden death; and seizures classified in life as epilepsy should be reviewed as possible arrhythmias [19].

In the cardiac arrest survivor, the PNDS calls for an exhaustive assessment in a tertiary centre: electrolytes, troponin, inflammatory markers, toxicology, ECG with high precordial leads, continuous electrocardiographic monitoring for at least 24 hours, exercise testing (preferably with abrupt onset, with analysis of repolarisation at the 4th–5th minute of recovery), echocardiography, cross-sectional imaging and coronary angiography, completed by cardiac magnetic resonance imaging to exclude myocardial infarction with angiographically normal coronary arteries (MINOCA), myocarditis or incipient cardiomyopathy and to look for fibrosis [19]. ECGs obtained immediately after resuscitation are interpreted with caution, because transient repolarisation changes may mimic acute coronary syndrome, long QT or Brugada syndrome in people who do not have these diseases, and post-arrest hypokalaemia is usual and does not explain the event. If the initial assessment is negative, it is repeated after an interval that depends on the hypothesis, and the ECG can be sensitised with the ajmaline test, the standing ECG and the mental stress test; the adrenaline test is no longer recommended routinely, because it is difficult to interpret and leads to excessive diagnoses of long QT [19]. The electrophysiological study is not systematic: programmed ventricular stimulation outside the suspicion of arrhythmogenic cardiomyopathy is of no use, because induced VF is non-specific, and the study is reserved for right ventricular voltage mapping, ablation of extrasystoles of Purkinje origin or exclusion of doubtful pre-excitation [19]. When the complete assessment is negative (idiopathic VF), an extended panel of arrhythmia and cardiomyopathy genes may be offered, after discussion with a geneticist, bearing in mind that the yield is low and interpretation difficult; family screening is then not routinely recommended, unless there are other sudden deaths or heart disease in the family, although the disease may be more visible in a relative than in the patient [19].

In the deceased, the personal history and a three-generation family history are collected, together with previous ECGs and imaging studies, whose interpretation may be revised in the light of the event, the recordings from emergency monitors and the external defibrillator and, where present, the memory of the pacemaker or ICD, interrogated as early as possible. Sampling for toxicology (peripheral and cardiac blood, urine, bile, gastric contents) is recommended in all cases, and detection of a substance excludes neither a cardiac cause nor its contribution [19]. The autopsy, complete and systematic, is performed by a team with experience in cardiac pathology; when a cardiac cause is suspected, the whole heart is sent to a cardiac pathologist, after external examination, transverse sections of the coronary arteries and, if possible, a single short-axis section near the apex, and histological examination after fixation includes at least 7 to 10 systematic samples (right and left ventricles, septum, coronary arteries) in addition to those directed at lesions; post mortem computed tomography and magnetic resonance imaging are useful but seldom available [19]. For the molecular autopsy, ideally two of three samples should be kept frozen (myocardium; spleen, liver or thymus; EDTA blood), preferably by rapid freezing at −80 °C without chemical treatment; a DNA and RNA stabilising reagent allows fresh tissue to be transported at room temperature for a few days, and, in rare cases, extraction may be attempted from formalin-fixed or paraffin-embedded tissue, from toxicological samples or from samples collected in life [19]. The cause of death is discussed at a multidisciplinary meeting with a pathologist, forensic physician, cardiologist and clinical geneticist.

With DNA available, genetic testing is guided by the autopsy hypothesis; if the autopsy is negative, a predefined panel of genes for inherited arrhythmias and cardiomyopathies remains indicated, which in France is agreed and updated by the CARDIOGEN network, and the result, in the absence of clinical orientation, is interpreted as an aetiological lead and not as proof [19]. Non-targeted tests (large panels, exome or genome) are not recommended for genetic counselling, because of the risk of misinterpreting variants of uncertain significance; such a variant cannot be used for family screening, and the priority becomes repeated clinical characterisation of relatives and the study of segregation over time [19]. In France, use of samples collected for judicial purposes requires authorisation from the public prosecutor, requested by the family or the forensic team in agreement with a reference centre; the consent of a single relative is sufficient to perform the analysis and transmit the result, and the conclusions are communicated to the family after the judicial seals are lifted, unless there is a local agreement with the prosecutor [19].

Clinical screening of first-degree relatives, with particular attention to both parents and, in the absence of one of them, extended to second-degree relatives, is indicated when the autopsy is negative and also, without autopsy, when the victim was younger than 45 years and the history offers no evident explanation (known disease capable of causing the event, previous anginal chest pain); the PNDS lists three situations: ventricular arrhythmia documented at the time of death, evidence of familial arrhythmia in the history of the victim or the family, and death before 45 years of age [19]. From 15 years of age, the complete assessment includes ECG, echocardiography, Holter, exercise testing with QT analysis at the 4th minute of recovery, ECG with electrodes in the 2nd and 3rd intercostal spaces, mental stress testing, standing ECG in adults (value debated in children) and, ideally, an ajmaline test, particularly if the baseline ECG suggests Brugada syndrome; magnetic resonance imaging is added according to the findings [19]. The PNDS points out that ajmaline can induce type 1 in 4–5% of healthy people, without definitive sensitivity and specificity data, and that the test may be negative in a child who develops the syndrome after puberty, which justifies the 15-year threshold and prior informed consent from the parents [19]. Before 15 years, the assessment is limited to ECG, Holter, echocardiography and exercise testing when age permits, repeated until the complete assessment at the intervals given in section 11.2. When the cause has been identified in the victim or in a relative, screening is directed at the disease concerned; when the victim's DNA does not exist, or testing was negative, and clinical screening is also negative, genetic testing of asymptomatic relatives is strongly discouraged, because a negative result does not exclude future disease and broad panels generate variants of uncertain significance, and the relatives' DNA may be stored for later analysis [19].

In the French multicentre experience on which the PNDS relies, complete clinical assessment of relatives combined with genetic analysis of the victim identified the cause in about 20% of autopsy-negative deaths; when the autopsy reveals macroscopic and microscopic cardiomyopathy, genetic analysis of the victim identifies the cause in about 35–40%, and the PNDS places the overall retrospective yield in deaths before 40–45 years at between 20% and 40% [19]. These figures come from reference-centre series with complete investigation and cannot be transposed to partial investigations. The sources diverge on three points: the age limit (autopsy recommended between 1 and 40 years in Clinical Cardiogenetics, family screening without autopsy up to 45 years in the PNDS); the position of the ajmaline test in relatives (offered, ideally, to all first-degree relatives aged 15 years or more in the 2022 PNDS, “to be discussed” in the 2021 PNDS on Brugada syndrome and advised by the 2025 EHRA consensus only in suggestive circumstances, such as sleep, fever or a suspicious ECG, after comprehensive assessment); and the duration of follow-up of negative relatives (up to 40 years in Clinical Cardiogenetics, up to 45 years in the PNDS) [4, 9, 19, 38].

5.6. Practical algorithm

1. Document the ECG (pattern and high leads), the circumstances (fever, drugs, electrolytes, ischaemia) and exclude phenocopies; echocardiography is the minimum investigation in all patients [9].
2. Spontaneous type 1: diagnosis; do not repeat provocation (ESC 2022, class III); stratify risk and initiate general measures [4, 17].
3. Type 2/3 or normal ECG with strong suspicion (cardiac arrest, arrhythmic syncope, first-degree relative of a definite patient without an SCN5A variant, relative of a SADS victim in suggestive circumstances): consider 12-lead Holter with high leads and sodium blocker testing according to EHRA [4].
4. Apply the Shanghai score; isolated induced type 1 requires clinical, familial or genetic support [6].
5. Sequence SCN5A in the proband and test relatives if a P/LP variant is identified [18].
6. Refer to a specialist centre with cardiology, genetics and counselling teams [42].

6. Differential Diagnosis

6.1. Brugada phenocopies and acquired causes

A phenocopy is a type 1-like pattern triggered by another cause. Clues include an identifiable underlying condition, pattern disappearance after resolution, no familial sudden death or first-degree relative type 1, absence of syncope, seizures or nocturnal agonal breathing, and a negative sodium blocker test [1]. Fever- or drug-induced patterns are not considered phenocopies; SCN5A sequencing may be considered in either [18].

The French PNDS orders the differential diagnosis pragmatically. The diagnosis is established only after ischaemia, pericarditis, myopathies, chest wall deformities and cardiac masses or compressions have been excluded, and all patients should have at least one echocardiogram. In practice, the most frequent confusions are right bundle branch block, which mimics the pattern without true ST elevation, and the former types 2 and 3, which are merely suggestive: in the absence of type 1 at follow-up or on provocation testing, the prognosis of these people is normal and Brugada syndrome should not be mentioned. When the pattern appears under a sodium channel blocker, particularly a class I antiarrhythmic, the drug is stopped, the ECG is repeated later and, if there is no spontaneous pattern, a provocation test may subsequently be performed to distinguish the effect of overdose from an underlying Brugada syndrome [9].

6.2. Other arrhythmic diseases and cardiomyopathies

7. Treatments and Risk Management Strategies

7.1. General measures for all patients and carriers

ESC 2022 recommends avoiding medicines inducing right precordial ST elevation (www.brugadadrugs.org), cocaine, cannabis and excessive alcohol, and promptly treating fever with antipyretics in all Brugada patients (class I, level C) [17]; AHA/ACC/HRS 2017 lists the same triggers in the text without a separate numbered recommendation [16]. BrugadaDrugs.org arose from a review of 506 publications and an international panel classifying medicines into four categories: avoid (18), preferably avoid (23), antiarrhythmics (4) and diagnostic medicines (4); most associations have level C evidence without randomised studies [11]. The same guidance applies to loss-of-function SCN5A carriers without a Brugada pattern [18, 28]. GeneReviews lists pattern-unmasking factors as fever, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic antagonists, tricyclic antidepressants, first-generation antihistamines and cocaine toxicity, and advises avoiding class IC and IA antiarrhythmics [2]. ECG monitoring is necessary during surgery and recovery; absence of targeted studies precludes general anaesthetic rules, requiring individual medicine assessment and controlled use [1, 2]. In an acute episode, fever, electrolyte disturbances and implicated agents are corrected, with admission at least until ECG normalisation [2].

The French PNDS turns these measures into a therapeutic education programme aimed at the patient and the family. Fever is treated actively with the usual means (paracetamol, tepid bath), and influenza vaccination is recommended to reduce febrile episodes [9]. This recommendation does not appear in the 2022 ESC guidelines or in GeneReviews and is contradicted, in the paediatric age group, by the Dutch consensus, which considers influenza vaccination not indicated in children with Brugada syndrome and recommends accompanying scheduled vaccinations with paracetamol [2, 17, 28]; the divergence results from weighing influenza fever against post-vaccination fever, without comparative studies in the sources consulted. The updated list of contraindicated drugs is provided (www.brugadadrugs.org, also given in appendix 5 of the PNDS), avoidance of acute alcohol intoxication and drugs (cannabis, cocaine) is recommended, and the patient is asked to seek medical attention again promptly in the event of syncope or suspicious symptoms, such as abrupt nocturnal awakening, occasional nocturnal enuresis or palpitations. Sports practice is not, as a rule, contraindicated; the patient should, however, reduce intensity progressively at the end of intense exertion, to avoid the post-exercise vagal reflex that accentuates the pattern and may increase arrhythmic risk, avoid sport in intense heat and maintain good hydration [9]. Accentuation of ST in the early recovery phase of exercise testing, described among the risk markers, is consistent with this recommendation [6].

7.2. Implantable cardioverter-defibrillator

The implantable cardioverter-defibrillator (ICD) is the only therapy with proven sudden death prevention efficacy in this syndrome [1, 6]. ESC 2022 and AHA/ACC/HRS 2017 classes and levels in the table were read in the original recommendation tables (ESC 2022, Recommendation Table 43 and Figure 33; AHA/ACC/HRS 2017, section 7.9.1.3) [16, 17].

Clinical Cardiogenetics describes post-arrest ICD as class IIa “primary prophylaxis”, but its own algorithm assigns class I after aborted sudden death; correct interpretation, confirmed in original tables, is class I secondary prevention (ESC 2022: I, C; AHA/ACC/HRS 2017: I, B-NR) [1, 16, 17]. The guidelines differ in alternative therapy strength: ESC assigns quinidine and ablation IIa, whereas the US guideline recommends them (I) for recurrent shocks or when ICD is unavailable; the US guideline also includes presumed arrhythmic syncope with spontaneous type 1 in class I, versus ESC IIa [16, 17]. Annual appropriate therapy rates are 2.2–3.7%, while complications reach 20–30% over 21–47 months, mainly inappropriate shocks from sinus tachycardia, supraventricular arrhythmias or T-wave oversensing, and lead dysfunction [6]. Programming a single VF zone above 210–220 beats/minute and longer detection times reduces unnecessary treatment of self-terminating arrhythmias [6]. T-wave oversensing is a recognised inappropriate-shock cause, usually resolved by reprogramming, although some need invasive intervention [1]. Subcutaneous ICD avoids endovascular leads when pacing is unnecessary but has high sensing screening failure rates because of T-wave amplitude; a French prospective multicentre Brugada subcutaneous ICD study was published in January 2026 with two accompanying editorials discussing programming versus signal acquisition, whose full texts were not consulted [45]. SCN5A variant presence and type should influence device choice because of conduction disease risk [18]. In elderly patients, a consensus conference accepted implantation for syncope with life expectancy of at least six months, and a follow-up study suggested considering non-implantation or non-replacement in patients remaining VF-free until 70 [1].

The French PNDS weighs the ICD indication against the device's own risks (lead fracture, infection, inappropriate shocks) and considers implantation indisputable after cardiac arrest and in syncope considered arrhythmic; in the latter situation, it aligns with the US guideline (class I) and not with the class IIa of the 2022 ESC guidelines [9, 16, 17]. In these patients, the discussion shifts to the type of device: the subcutaneous ICD reduces the risk of lead fracture, relevant in a young and active population, and of endovascular infection, but does not allow pacing and, despite improvement, still causes more inappropriate shocks than the transvenous device. In asymptomatic spontaneous type 1, the PNDS estimates arrhythmic risk at 1% per year, cumulatively 10% at 10 years, and considers the indication debatable; this value is higher than the 0.4% per year observed in the Italian prospective study of 1,149 asymptomatic individuals and lies at the upper limit of the ranges of the 2026 consensus, which illustrates how these estimates depend on the cohort and the period [6, 9, 46]. The decision whether to implant should always be shared, after complete information on the expected benefit and on the medical complications and non-medical consequences, such as insurance and occupational activity. In atypical syncope considered probably reflex, the PNDS proposes monitoring with an implantable loop recorder, of very low risk [9].

7.3. Pharmacological treatment

Pharmacological management seeks to rebalance action potential phase 1 currents by inhibiting transient outward current or increasing sodium and calcium currents, for three uses: electrical storm treatment, episode prevention in ICD carriers with multiple shocks, and an ICD alternative when contraindicated, infeasible, inaccessible or declined [1].

Quinidine is a class IA antiarrhythmic with I_to and I_Kr blocking action and is the most studied drug in Brugada syndrome; GeneReviews gives 1–2 g per day for prevention of primary manifestations and describes restoration of the ST segment and reduction in the incidence of arrhythmias [1, 2]. The 2022 ESC guidelines include Brugada syndrome among the indications for quinidine in the table of antiarrhythmics for adults, with 600–1,600 mg per day orally and a loading dose of 200 mg every 3 hours until effect, with a maximum of 3 g in the first 24 hours, without specifying the salt [17]; GeneReviews gives neither a maximum dose nor a paediatric dose [2]. The 2023 pharmacological review summarises the available evidence: quinidine bisulfate at a mean dose of 1,483 ± 240 mg in 25 patients with inducible VF, with prevention of reinduction in 22 (88%), no arrhythmic events over 6 months to 22 years of follow-up and adverse effects in 36%; hydroquinidine 600–900 mg per day in 35 people, with prevention of inducibility in 76% of the reassessed asymptomatic individuals; electrophysiology-guided hydroquinidine 600 mg per day in 44 asymptomatic individuals with inducible VF, of whom 77% became non-inducible, with an overall annual arrhythmic event rate of 1.04% (95% CI 0.00–2.21) and no events in the treated group; a Spanish national survey with quinidine bisulfate (591 ± 239 mg/day) and hydroquinidine (697 ± 318 mg/day) in 29 ICD patients, 66% of whom remained free of appropriate shocks over 60 ± 41 months; and a comparison of 53 patients treated with hydroquinidine at a mean dose of 439 ± 115 mg per day with 441 matched controls, with a 26% reduction in the overall risk of an arrhythmic event and a fall in the annual recurrence rate from 14.7% to 3.9% in the 123 patients with aborted sudden death (HR 0.33; 95% CI 0.12–0.92) [12]. The only randomised, double-blind, crossover trial, QUIDAM, included 50 ICD patients in two 18-month phases: during the 36 months of follow-up there was one appropriate shock (0.97% events per year), one self-terminating VF and one inappropriate shock on placebo, and no arrhythmic event on hydroquinidine, but the difference was not statistically significant because the event incidence was very low; 68% of participants had adverse effects, mainly gastrointestinal, which led to discontinuation in 26%; the drug prolonged the QTc (409 ± 32 ms to 433 ± 37 ms) and increased dispersion of repolarisation without altering J-point elevation [47]. These results require cautious interpretation: the absence of events in a small sample over a short period does not demonstrate efficacy, and the 2026 consensus observes that definitive efficacy was not established because there were no events in the crossover phases [6]. Adverse effects are dose-dependent, the associated diarrhoea can be treated with colestyramine, allowing therapy to be continued, and availability of the drug is limited in many countries [6]. Quinidine used for this indication is off-label: in the United States, the prescribing information for quinidine sulfate tablets approves conversion and prevention of recurrence of atrial fibrillation or flutter, suppression of documented, recurrent ventricular arrhythmias judged life-threatening and treatment of severe Plasmodium falciparum malaria, but does not mention Brugada syndrome; the same label carries a boxed warning on increased mortality in non-life-threatening arrhythmias, describes the risk of torsades de pointes and cinchonism, places pregnancy in category C and states that the safety and efficacy of antiarrhythmic use in the paediatric age group have not been established [14]. The label does not set a regimen for ventricular arrhythmias: it states that the regimens described are similar to that for prevention of AF recurrence, starting at 200 mg of quinidine sulfate (166 mg of quinidine base) every 6 hours (800 mg/day), with cautious increases guided by the serum level, no maximum dose defined in the label, and reduction if the QRS or QTc increase to 130% of baseline (with QTc >500 ms); this label regimen serves as a comparison, and the reference dose in Brugada syndrome is that of the 2022 ESC guideline (600–1,600 mg/day in adults), close to the 1–2 g/day of GeneReviews, both higher than the label's starting dose [2, 14, 17]. No medicine containing quinidine or hydroquinidine is centrally authorised in the European Union for this disease: the only quinidine product on the European Medicines Agency's list of medicines is the dextromethorphan–quinidine combination, authorised for pseudobulbar affect and with “withdrawn” status [15].

The French PNDS starts from the same finding, that no drug has demonstrated preventive efficacy, and restricts the place of hydroquinidine: it reduces the frequency of events in ICD carriers with frequent arrhythmic events, has no demonstrated benefit in primary prevention, and the frequency of adverse effects and imperfect efficacy limit its use [9]. The document notes that Israeli teams use it guided by electrophysiological study, that the only randomised study lacked statistical power, owing to few patients and few events, and that the reduction in inducibility observed on hydroquinidine did not translate into a demonstrated reduction in events; it admits a particular place in children and in people who refuse an ICD, and requires blood level measurement to adjust the dosage, repeated annually [9]. The PNDS does not give a dose. In the absence of a guideline dose for hydroquinidine, the reference is the French summary of product characteristics (SmPC) of Sérécor® (hydroquinidine hydrochloride 300 mg, prolonged-release capsules, revised by the ANSM in March 2025): one capsule in the morning and another in the evening, 12 hours apart (600 mg per day), and, if arrhythmia control is incomplete, two capsules twice a day (1,200 mg per day, the highest dose provided for in the SmPC); target plasma concentration of 3 to 6 µmol/L by high-pressure liquid chromatography, with measurement recommended in moderate or severe renal impairment and with CYP3A4 inhibitors or inducers; initiation at low doses with electrocardiographic monitoring [13]. These values coincide with the 600–900 mg per day of the European studies in adults and are below the mean dose of 1,483 ± 240 mg of quinidine bisulfate in the first series summarised in the 2023 review, with no direct equivalence between the two salts [12]. The SmPC states that paediatric safety and efficacy have not been demonstrated, with no data available, which contrasts with the paediatric place admitted by the PNDS and makes any prescription in children a use outside the SmPC conditions; it advises against use in pregnancy owing to lack of data and asks that breastfeeding be avoided during treatment; it contraindicates the drug in AV block or sinus node disease without a pacemaker, in complete bundle branch block and other marked intraventricular conduction disturbances, in long QT, in torsades de pointes, in heart failure and in combination with other torsadogenic drugs; and it describes very frequent diarrhoea, cinchonism, thrombocytopenia, immunoallergic hepatitis and proarrhythmic potential [13]. The conduction contraindications are relevant in carriers of SCN5A variants, who frequently have conduction delay, and reinforce the usefulness of the ICD, which allows backup pacing, in these patients [13, 35]. Among its efficacy data, the SmPC refers to observational studies, registries and case series in Brugada syndrome, short QT syndrome and early repolarisation, and states that there are no randomised or blinded studies in inherited arrhythmic diseases, a wording that does not take account of the double-blind crossover trial QUIDAM, which had no significant result [13, 47].

Isoproterenol (isoprenaline) is first-line treatment of electrical storm; GeneReviews gives an infusion of 1–3 µg per minute before other antiarrhythmics [2]. In the chapter on early repolarisation syndrome, the 2013 HRS/EHRA/APHRS consensus describes starting at 1.0 µg per minute, aiming to increase the heart rate by 20% or reach more than 90 beats per minute, titrating according to haemodynamic response and suppression of arrhythmias [43]. The French PNDS sets a higher target, a heart rate above 100 beats per minute during the arrhythmic storm, without giving the infusion rate; in practice, the rate is titrated within the GeneReviews range of 1–3 µg per minute until that target is reached [2, 9]. This too is off-label use: the US label for isoproterenol hydrochloride injection approves improvement of haemodynamic status in distributive shock and in shock due to reduced cardiac output and bronchospasm during anaesthesia, with a recommended initial dose of 0.5 to 5 µg per minute by intravenous infusion in shock; the adverse effects described include tachycardia, tachyarrhythmias, palpitations, angina, ventricular arrhythmias, pulmonary oedema, headache, tremor and nausea [48]. Deep sedation and hypothermia are resources described in refractory storms, with inconsistent results in early repolarisation syndrome, and heart transplantation has been needed in extreme cases [6].

Other medicines reported effective in series and cases include cilostazol, bepridil, denopamine, orciprenaline and quinine sulfate; cilostazol and bepridil are available mainly in Japan and few other countries [1, 6]. Cilostazol plus bepridil suppressed VF recurrences and reduced J-wave amplitude in a small early repolarisation syndrome ICD series [43]. Clinical Cardiogenetics lists disopyramide as effective, but GeneReviews and BrugadaDrugs classify it among class IA agents to avoid; this contradiction is resolved in favour of GeneReviews and the BrugadaDrugs panel [1, 2, 11]. Amiodarone, beta-blockers and calcium channel blockers should be avoided, and class IA (ajmaline, procainamide) and IC (flecainide, propafenone, pilsicainide) sodium blockers are contraindicated outside diagnosis because they unmask the pattern and may induce arrhythmias; provocation arrhythmia rates range from 0% to 17.8% [1]. In children, the Dutch consensus contraindicates amiodarone and sodium blockers recommended by general paediatric advanced life support protocols, treats arrhythmias and storms with isoproterenol, permits a beta-blocker for fever-associated monomorphic VT, and considers quinidine in highly symptomatic patients with sparse paediatric evidence [28].

7.4. Comparative regulatory status

No medicine has an FDA or EMA authorisation whose indication is Brugada syndrome. An authorisation for another indication does not guarantee reimbursement or availability: quinidine is described as unavailable in many countries, and access to ajmaline, cilostazol and bepridil varies by region [6]. No specific access or reimbursement data were located for Portugal (INFARMED) or Brazil (ANVISA, CONITEC) in the sources consulted, which does not mean that national documents on these medicines do not exist. In France, the PNDS also serves as the basis for the care protocol drawn up between the attending physician, the specialist and the medical adviser of the Assurance Maladie to request exemption from the patient's co-payment (ticket modérateur) as an “affection hors liste”, in cases that do not fall under a listed long-term condition (ALD) [9].

7.5. Arrhythmogenic substrate ablation

Catheter ablation began with triggers: triggering premature beat ablation was described in three patients in 2003, but spontaneous beat rarity made this impractical and shifted attention towards substrate [1, 6]. In 2011, a nine-patient symptomatic study constructed three-dimensional endocardial and epicardial right ventricular maps: abnormal substrate ablation normalised ECGs in eight and none had recurrent VF over mean 20-month follow-up [1]. The following year, ten symptomatic patients underwent the same technique, with ECG changes in three of four with VF storm and no recurrence at 30 months [1]. In 135 symptomatic ICD patients published in 2017, substrate elimination normalised ECGs and removed inducibility; ECGs remained normal even after ajmaline except in two, successfully re-treated, over median 10-month follow-up [1, 50].

Substrate lies in right ventricular outflow tract epicardium in virtually all patients; approximately 29–30% also have inferior RV epicardial substrate and approximately 2% posterolateral LV epicardial substrate, often with ECG early repolarisation [6, 23]. Sodium blockers reveal part of it, doubling treatment area; EHRA therefore advises procedural provocation, preferably ajmaline [4, 6].

The limitations of these data should be made explicit. Both trials are small, open-label, were stopped early for apparent superiority — which tends to overestimate the effect — and included only highly symptomatic ICD patients, so they do not allow extrapolation to asymptomatic individuals. The relative reduction (HR 0.288 in BRAVE) should be read alongside the residual absolute rates of each study and does not allow the two trials to be ranked against each other, or compared with the quinidine results, because the populations and outcomes differ. The BRAVO registry is observational and its VF-free survival of 95% at five years refers to the time after the last ablation, not after the first. The 2026 consensus considers that the two trials support epicardial ablation as first-line therapy for recurrent VF, particularly where quinidine is unavailable or poorly tolerated, and lists as open questions whether complete ablation can replace the ICD, whether asymptomatic individuals should be considered for prophylactic ablation and whether extensive ablation increases the risk of scar-related reentrant VT or impairs right ventricular function [6]. The French PNDS, written in 2021, before publication of the two randomised trials, acknowledged good results of epicardial outflow tract substrate ablation in repeated VF but, given the still limited experience, reserved it for patients already carrying an ICD, without demonstrated efficacy in primary prevention, and anticipated a broadening of indications; the position of the 2026 consensus, which places it as first line in recurrent VF, is later and rests on the 2025 trials [6, 9]. A randomised sham-controlled trial conducted at the Hospital das Clínicas of the University of São Paulo, Brazil, with 20 participants, is registered as completed in April 2026, with electrophysiological primary outcomes (activation-recovery interval and area of abnormal potentials in the first 30 minutes) and no published results at the date of this review [51]. In early repolarisation syndrome, a multicentre study showed that 39 of 43 patients (91%) remained free of VF recurrence after 31 ± 26 months, with substrate ablation in most and ablation of Purkinje triggers in patients without depolarisation abnormalities [6]. In children, the short- and long-term effects of epicardial ablation are unknown and the Dutch consensus admits it only in an experimental setting, for uncontrollable arrhythmias [28].

7.6. Developments in the past twelve months and research

None represents a marketing authorisation application, a human medicines committee opinion or regulatory decision: the consulted sources contain no ongoing Brugada medicine regulatory submission. The European orphan designation search could not be completed because the downloaded file was unreadable; this recorded limitation is not evidence of no designations. Preclinical approaches include iPSC-derived cardiomyocytes reproducing SCN5A loss of function for compound testing, limited by cellular functional immaturity, and mathematical platforms seeking improved translation of their results [1].

8. Reproductive Options and Family Counselling

8.1. Inheritance and recurrence risks

Brugada is autosomal dominant except for one family with an X-linked KCNE5 variant whose gene–disease validity is disputed by ClinGen [2, 8]. Most patients have an affected parent or other close relative, and de novo variants are uncommon, approximately 1% [2]. Each carrier's child has a 50% chance of inheriting the variant, but less than 50% of developing disease because of reduced penetrance and other genetic and environmental influences; reduced penetrance and variable expressivity define this syndrome [2]. Sibling risk is 50% with an affected or asymptomatic carrier parent; if the variant is undetectable in either parent's leucocyte DNA, estimated risk is approximately 1% from theoretical germline mosaicism, not excluded by leucocyte testing [2]. Apparently negative family history is inconclusive, potentially reflecting unrecognised disease, incomplete penetrance, early parental death before symptoms or late onset; it is confirmed only when the proband has a known variant absent from both parents [2].

Parental evaluation includes ECG, attention to familial sudden death and targeted molecular testing if the proband's variant is known [2]. A pathogenic SCN5A variant alone does not justify prophylactic ICD implantation but should prompt more active management with clinical risk markers such as arrhythmic syncope [18].

The French PNDS states the same rule explicitly: the diagnosis is clinical, based on the ECG, and genetic information only complements it. A relative carrying the familial variant with a normal ECG should not be considered affected and, conversely, a non-carrier relative may have the syndrome; in families with an SCN5A variant, penetrance in carrier relatives is below 50%, and non-carrier relatives who develop the disease are found relatively often, which the document attributes to a complex, probably multifactorial architecture, with a contribution from common variants [9]. Family screening can therefore never be limited to genetic testing and always includes clinical assessment with an ECG [9].

8.2. Cascade screening

The two approaches diverge on the extent of pharmacological provocation. The PNDS proposes it, as the ideal means, for all first-degree relatives from 15 years of age, arguing that only a negative test allows the person to be reassured and follow-up of their offspring to be stopped, because a normal ECG does not exclude the disease [9]. The 2025 EHRA consensus advises it in first-degree relatives of probands without an SCN5A variant, with shared decision-making, admits it in carriers of the familial variant only with a clear clinical rationale and in a specialised centre, and does not support systematic provocation of genotype-negative relatives in families with a variant [4]. The difference has practical consequences: a positive test in an asymptomatic person does not change treatment, but creates a diagnosis with implications for insurance and working life; the PNDS requires that the asymptomatic person be informed, before the test, that a positive result does not change treatment [4, 9].

In children from P/LP SCN5A families, the Dutch consensus advises genetics consultation, potentially during pregnancy, to discuss presymptomatic testing; postnatal cord blood may be used for the familial variant. If parents decline, follow the child as a carrier. Carrier children undergo paediatric cardiology assessment preferably before first vaccination, with standard and high-lead ECGs and reassessment during fever [28]. Genetic testing is unhelpful in children from families without an SCN5A variant; in a retrospective cohort of 97 at-risk children, none from variant-negative families developed fever type 1. A single assessment after birth or familial diagnosis is recommended, with postpubertal reassessment and possible provocation to confirm or exclude diagnosis [28].

8.3. Prenatal diagnosis and preimplantation genetic testing

Once the familial variant has been identified, prenatal diagnosis and preimplantation genetic testing (PGT) are technically possible, and GeneReviews stresses that the use of prenatal diagnosis is generally considered a personal decision, on which differing views may exist among professionals and within families [2]. The Clinical Cardiogenetics chapter devoted to this subject provides the available European data: the European Society of Human Reproduction and Embryology has collected PGT data since 1997, the first cardiogenetic case described was Brugada syndrome in 2006, and between 2006 and 2010, 24 PGT cycles for inherited heart diseases were performed in Europe, of which 7 were for Brugada syndrome, 7 for hypertrophic cardiomyopathy, 4 for long QT syndrome, 2 for arrhythmogenic cardiomyopathy, 2 for catecholaminergic polymorphic ventricular tachycardia and 1 for dilated cardiomyopathy and 1 for congenital cardiomyopathy [53]. In the Dutch consortium, between 1995 and 2017, 3,280 couples were referred for PGT, of whom 45 (about 1%) had an inherited heart disease; 11 (24%) for a channelopathy, including 2 couples with Brugada syndrome, 1 with idiopathic ventricular fibrillation associated with the DPP6 risk haplotype and 3 with long QT syndrome. After intensive counselling, 11 couples (with cardiomyopathies and idiopathic ventricular fibrillation) proceeded with the procedure, and the others opted for natural conception without testing, donor gametes or adoption; the two couples with Brugada syndrome did not undergo PGT [53]. The Dutch eligibility criteria require a recurrence risk above 10%, severe disease, a known variant classified as pathogenic or likely pathogenic, technical feasibility, conditions for in vitro fertilisation, female age below 40 years and a body mass index of up to 35 [53]. Prenatal diagnosis in these diseases is rare: between 2001 and 2015, in the Netherlands, 8 procedures were performed for inherited arrhythmias and cardiomyopathies, representing 0.3–0.7% of the annual total of prenatal diagnoses; in all families there was a severe phenotype or a family history of sudden death [53]. Non-invasive prenatal diagnosis on circulating fetal DNA exists for a limited number of monogenic diseases, but not for inherited heart diseases [53]. The French PNDS considers that, given the usually favourable prognosis and the complexity of the genetic model, there is no indication for prenatal diagnosis or preimplantation diagnosis, except in very particular situations: families with a particularly high rate of sudden death and good cosegregation between the variant, usually in SCN5A, and the disease; there is no experience with variants in other genes [9]. This position is consistent with the Dutch eligibility criteria and with the decision of the two Dutch couples with Brugada syndrome who did not proceed to PGT [53]. The 2022 PNDS on sudden death in the young applies the same reasoning to arrhythmic diseases as a whole: as most can be treated effectively, prenatal and preimplantation diagnosis arise, very rarely, only in families with a particularly high rate of sudden death and a disease with poorly effective treatment, with the examples of long QT type 3, some forms of catecholaminergic ventricular tachycardia and sudden deaths associated with DPP6 [19].

8.4. Pregnancy, peripartum and perioperative settings

Hormonal changes as pregnancy precipitants are discussed with limited data. Pregnancy involves autonomic and haemodynamic changes, and oestrogen and progesterone fall peripartum; some authors suggested higher hormone levels increase arrhythmic risk in individual cases, while others described uneventful pregnancy and puerperium [1]. The largest published study is a single-centre retrospective analysis of 104 women and 219 deliveries: 15 miscarriages, one infant dying suddenly at night three months after birth, six women reporting at least one pregnancy syncope, no arrhythmias among three with previous ICDs, no pregnancy events among four with previous aborted sudden death, and, among 24 with syncope outside pregnancy, 18 asymptomatic and 6 with recurrent syncope; over mean 298.9-day follow-up, two received appropriate shocks. Authors concluded that severe events were not more frequent in pregnancy or peripartum and that miscarriage and sudden infant death rates require further studies to confirm or exclude association [54]. Multidisciplinary cardiology and anaesthesiology care is required [1].

For pregnancy arrhythmias, GeneReviews describes suppression of recurrent ventricular tachyarrhythmia and ECG normalisation with low-dose intravenous isoproterenol followed by oral quinidine, stating that quinidine is not known to be teratogenic and is preferred for pregnancy arrhythmias [2]. This must be read alongside US labelling assigning pregnancy category C without adequate controlled pregnancy studies, reporting one newborn with maternal-equivalent serum levels and no apparent adverse effect, and amniotic fluid levels approximately three times serum levels [14]. Isoproterenol labelling states that prolonged pregnancy experience identified no major malformation or miscarriage risk but describes labour risks through inhibited contractions and delayed second stage, advising avoidance during labour and when maternal blood pressure exceeds 130/80 mmHg [48]. ECG monitoring continues in all surgical settings including delivery [2].

The French PNDS, relying on the same single-centre study, finds no signal of particular risk during pregnancy and delivery, situations that are infrequent in a male-predominant disease, and recalls the precautions with contraindicated drugs, particularly if general anaesthesia is needed for caesarean section [9, 54]. Given the 50% risk of transmission, it recommends an ECG in the newborn in the days following birth, although the risk associated with the syndrome at that age is very low, and it does not provide for specific maternal surveillance in the postpartum period or restrictions on breastfeeding [9]. This absence of restriction refers to the disease: if the mother is taking hydroquinidine, the French SmPC advises against the drug in pregnancy and recommends avoiding breastfeeding, owing to passage into breast milk [13].

8.5. Counselling content

Genetic counselling should include the mode of transmission and reduced penetrance, the difference between a variant carrier and an affected person, the meaning of a variant of uncertain significance, the immediate practical consequences (fever control, list of drugs to avoid, limitation of alcohol consumption, what to do in the event of syncope), identification of at-risk relatives, the availability and limitations of provocation testing and reproductive options [2, 18]. The ideal time to determine genetic risk and discuss prenatal diagnosis and PGT is before pregnancy, and counselling should be offered to affected or at-risk young adults [2]. In probands without a molecular diagnosis, DNA banking should be considered, because technology and interpretation evolve [2]. It should be explained that genetic testing, even when positive, does not in itself change decisions about a device, and that knowledge of the genotype serves mainly to identify at-risk relatives, direct surveillance and release non-carriers from unnecessary follow-up [1, 18]. The French PNDS adds two cautions: that, in families with an SCN5A variant, a non-carrier may develop the disease, which prevents discharging a relative on the basis of the genetic result alone, and that the diagnosis almost always arises in healthy people who did not consider themselves at risk, with a psychological impact compounded by the risk of transmission to children. Psychological support is therefore part of care from the announcement of the diagnosis, by a clinical psychologist, without being systematic; in France, the Centre National de Ressources Psychologiques (CNRP) of the CARDIOGEN network provides occasional support and guidance and maintains a national directory of psychologists trained in inherited arrhythmic diseases [9]. After the sudden death of a young person, prolonged grief affects about 21% of first-degree relatives, compared with about 7% of the bereaved population in general, and post-traumatic stress symptoms occur in 44%; in a survey of bereaved parents, almost three quarters wanted access to professional psychological support, the least satisfied need [19]. The 2022 PNDS therefore recommends offering psychological support at all stages, from bereavement to the announcement that a parent transmitted the responsible variant, with the guilt that may accompany that announcement, and discussing with the family from the outset both possibilities, that of finding a cause and that of not finding one [19].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each number measures

None is a national prevalence, and no hospital series should be converted to population prevalence. True prevalence is probably underestimated because some patients are asymptomatic and the ECG pattern intermittent [1].

9.2. Geography, ancestry and founder effects

Disease occurs worldwide but is more prevalent in East and particularly Southeast Asia; paradoxically, P/LP SCN5A variants are less frequent there (5–10%) than in European-ancestry populations (approximately 20%) [6]. Thai studies partly explain this through ancestry-specific low-frequency variation: missense p.(Arg965Cys) in 6.5% of cases versus 0.4% of ancestry-matched controls, and a channel-density-reducing intronic SCN5A enhancer (RE5) noncoding variant in 3.9% versus 0.06%, with an odds ratio of 45.2. Heterozygous introduction into iPSC-derived cardiomyocytes reduced variant-allele SCN5A expression and Nav1.5 current density by 30%, and 89% of carriers had cardiac arrest [6, 29]. GeneReviews identifies p.(Arg965Cys) as a Thai founder variant; its conflicting ClinVar classification illustrates difficulties transferring European-ancestry-based classifications [2, 31].

The Dutch SCN5A founder 1795insD (c.5382_5384dup) produced the first described overlap syndrome and one of the world's best-characterised families, combining Brugada, conduction disease and QT prolongation [26]. European, Japanese, Thai and Taiwanese GWASs suggest shared polygenic architecture across ancestries, with susceptibility allele frequency differences and potentially unidentified ancestry-specific variants [6].

First arrhythmic event age was comparable in White and Asian SABRUS patients (median 43), but male:female ratios differ: 9:1 in Asians, 7:3 in Caucasians [6, 10]. Febrile events showed an ethnic pattern: 83% of those with febrile events were Caucasian, with no Asian febrile events below 24 [37]. A Taiwanese study above 55 found Brugada pattern prevalence above the global mean, attributed to Southeast Asian endemic expression, without overall or cardiac mortality differences between pattern-positive and pattern-negative individuals [1].

The main sources contained no Portuguese prevalence or cohort data; Brazil contributed the sham-controlled randomised Hospital das Clínicas, University of São Paulo trial, completed April 2026 without published results [51]. Absence from consulted sources does not establish that regional publications do not exist; no targeted geographical searches were performed.

9.3. Special populations

Disease is less clinically apparent in children, but SCN5A carriers are more frequent among probands (47–67%); fever is the main precipitant and febrile events concentrate in early life [28, 37]. Male predominance is absent before puberty and girls may be more symptomatic [1, 6]. In older patients, first-event and recurrence probabilities decrease after 70, with reported VF of 0.3% annually above 60; provocation and device decisions require individualisation because of sparse specific data [1, 6]. Women's annual event rate is 0.25–0.7%, with less spontaneous type 1 and induced VF than men, but overlapping risk factors [6].

In the school setting, the French PNDS provides, for affected children, an individualised reception plan (PAI, projet d'accueil individualisé) drawn up with the school health service, centred on two instructions: treat fever actively and call emergency medical services immediately in the event of syncope. These measures should not prevent normal school integration, and school sport is permitted, except contact sports in children with an ICD. Follow-up also involves school doctors, for children, and occupational physicians, for adults, with the aim of avoiding school, social and professional isolation and of supporting the family in dealings with insurers [9].

9.4. Reference networks and patient organisations

The relevant European network is ERN GUARD-Heart for rare and complex cardiac diseases, including coauthors of the 2026 consensus [6]. GeneReviews lists Fundació Brugada (Spain, brugada.org), the Sudden Arrhythmia Death Syndromes (SADS) Foundation (sads.org), Canada's SADS Foundation (sads.ca) and MedlinePlus [2]. The Oxford Desk Reference adds SADS UK (sadsuk.org.uk) and Arrhythmia Alliance (heartrhythmalliance.org) [42]. BrugadaDrugs.org, maintained by an international expert panel from Amsterdam's academic medical centre cardiology department, is the professional and patient reference for medicines to avoid, extending advice to sodium channel loss-of-function carriers without a Brugada pattern [11]. Care should be provided by a dedicated team of specialist cardiologists, clinical geneticists, genetic counsellors and other support, also reviewing at-risk relatives [42].

In France, care is organised in the multisite reference centre for inherited arrhythmic diseases, with a coordinating site in Paris (Hôpital de la Pitié-Salpêtrière) and sites in Paris (Bichat, Necker-Enfants Malades, Hôpital Européen Georges-Pompidou, Robert-Debré), Nantes (coordinator of the PNDS), Bordeaux and Lyon, and in a network of 29 competence centres that includes Guadeloupe and Réunion, integrated into the CARDIOGEN rare disease health network. The PNDS was drawn up according to the 2012 HAS method by the reference centre, with the participation of the competence centres and of the Association Française des Maladies Héréditaires du Rythme Cardiaque (AMRYC), and relies on the ESC recommendations; follow-up is shared between the coordinating physician of the centre, the attending cardiologist and the general practitioner [9]. The 2022 PNDS on sudden death in the young, coordinated by the same Nantes centre, was drawn up with AMRYC and the association Les Maux du Cœur and assigns a central role to the general practitioner, because the search for a cause often arises long after the death, even when it is old, and the offer of family screening depends on it; it also recalls that aneurysm rupture, often invoked to families, can only be accepted as the cause after an autopsy [19].

10. Illustrative Clinical Case

Frosio and colleagues published this case in Europace in February 2026 in a translational study combining clinical assessment, cellular electrophysiology, computational modelling and structural analysis [32].

A 67-year-old man without known medical history was admitted to intensive care after cardiac arrest. He reported mild asthenia and dizziness, with Glasgow Coma Scale 15; temperature, blood pressure, heart rate, respiratory rate and oxygen saturation were normal, with significant hypokalaemia at 2.5 mEq/L, subsequently corrected. Admission 12-lead ECG showed type 1 with V1–V2 J-point elevation, a small V1 ST notch and no reciprocal ST depression in complementary leads. Echocardiography and angiography excluded structural and coronary disease. Over the previous two days he had viral gastroenteritis, fever on day one, nausea, vomiting and diarrhoea. An ICD was implanted. One-month post-discharge ECG confirmed sinus rhythm with V1 type 1 and prolonged QTc above 440 ms. Genetic testing identified heterozygous SCN5A p.(Ser805Leu), also present in his 29-year-old son and 34-year-old daughter; ajmaline 1 mg/kg over 5 minutes induced type 1 in the son but not daughter. There was no previous personal or family Brugada history [32].

Functional studies showed two heteromeric WT/S805L channel behaviours: normal at −80 mV and loss of function at more negative potentials, −100 to −120 mV. In isolated RV outflow tract cardiomyocytes, hypokalaemia (external potassium reduced from 3.5–5 mM to 2.5 mM) and, less strongly, bradycardia (stimulation reduced from 4 to 1 Hz) hyperpolarised diastolic potential, favouring sodium current loss of function; computational and molecular modelling identified the structural determinant. Authors interpret vomiting- and diarrhoea-induced hypokalaemia plus bradycardia as permitting arrhythmic expression of a variant asymptomatic during normokalaemia; they note circadian potassium variation, lowest from late afternoon to mid-night, coinciding with greatest disease expression [32]. Original figures, particularly Figure 1, show the arrest ECG, admission type 1, channel topology and variant location, pedigree and children's ajmaline tests; they are available in the open-access article (PMC12886553) and not reproduced here [32].

Three observations delimit interpretation. First, p.(Ser805Leu), c.2414C>T on NM_000335.5, is a ClinVar VUS with criteria from multiple submitters without conflicts; authors' functional and segregation data support pathogenicity as research rather than formal reclassification, so clinical reporting remains VUS [31, 32]. Second, ICD implantation is secondary prevention after arrest, concordant with guidelines (ESC 2022 I, C; AHA/ACC/HRS 2017 I, B-NR, the latter for spontaneous type 1) [16, 17], but the proposed hypokalaemia mechanism does not make electrolyte correction a device alternative [12]. Third, negative ajmaline in the carrier daughter does not exclude disease and illustrates sex-dependent phenotype, discussed with testosterone's effect on ST elevation; it does not alone justify definitive discharge [4, 32].

11. Prognosis and Long-Term Follow-up

11.1. Risk stratification

Annual risk varies markedly by presentation. Prior VF or aborted arrest carries annual new-event incidence of 7.7–14.2%; syncope carries 1.9–2.2%, with hazard ratios 1.48–3.7, diluted by non-arrhythmic syncope, while firmly suspected arrhythmic syncope carries 5.5% annually; overall symptomatic risk is described as 3–15%, and asymptomatic VF incidence approximately 0.4% annually [6].

The prospective Italian study of 1149 asymptomatic Brugada-pattern patients, followed at least annually for 2–22 years, is the strongest reference for asymptomatic management: median follow-up was 6 years (4–9), with 17 arrhythmic events (1.5%; 0.2% annually), 16 among 539 spontaneous type 1 patients (0.4% annually) and 1 among 610 drug-induced-only type 1 patients (0.03% annually; p < 0.001). Among 339 spontaneous type 1 patients undergoing electrophysiology, positive studies yielded 7 events in 103 (0.7% annually) versus 4 in 236 negative studies (0.2% annually; p = 0.025); of 200 declining testing, 5 had events (0.4% annually). One device-related death occurred [46]. Two implications follow: overall asymptomatic risk is low, relevant to young patients with long life expectancy, but spontaneous type 1 with positive electrophysiology confers higher risk; induced-only patients have minimal risk and should retain 12-lead Holter follow-up to detect spontaneous type 1 [46].

Multiparametric scores seek to overcome individual variable limitations. PAT (Predicting Arrhythmic evenT), derived from a 67-study meta-analysis of 7358 patients (37% symptomatic, 63% asymptomatic; 70% spontaneous type 1), combines nine factors, seven ECG-based, and was validated in relatively small internal and external cohorts, with 95.5% sensitivity and 89.1% specificity for a first major arrhythmic event, outperforming Sieira and Shanghai; the 2026 consensus advises caution pending further validation [6, 55]. Combining factors is recommended rather than implanting a device in an asymptomatic patient on one marker alone [6].

Prior arrest without spontaneous type 1 is not reassuring: early VF recurrence resembles spontaneous type 1, and predeath ECGs in victims with familial Brugada evidence are more often normal than type 1 [6].

11.2. Surveillance

Intervals diverge between sources. The French PNDS sets an annual visit for all diagnosed patients, including asymptomatic individuals, with ECG at the three lead heights; GeneReviews proposes ECG every one to two years for relatives and carriers; the Dutch consensus spaces the assessment of children to every one to three years in those diagnosed and every three years in carriers, with additional ECG during fever; and the Italian prospective study recommends, in patients with an induced-only pattern, repeated ECGs and 12-lead Holter, which the PNDS does not consider systematically useful [2, 9, 28, 46]. The PNDS justification for not generalising Holter and exercise testing is the rarity of events, even in symptomatic patients; that of the Italian study is the detection of intermittent spontaneous type 1, which changes the risk class. The PNDS also points out that the numerous clinical and paraclinical parameters proposed for risk stratification have low and variable reproducibility between populations and studies, which are generally small [9].

In the period after the sudden death of a relative, family members without a diagnosis after complete assessment are generally followed up to 40 years of age; if the assessment of the victim and relatives provides evidence of heart disease, a causal variant is found in more than 5% of first-degree relatives [38]. The 2022 French PNDS extends repetition to 45 years, every 3–5 years, and acknowledges that a complete and negative assessment of the victim and the relative is reassuring, making specific follow-up unnecessary, whereas incomplete investigation of the victim justifies periodic ECG and echocardiography, because some cardiomyopathies are only expressed at 50–60 years [19, 38].

11.3. Prognosis with treatment

ICD prevents sudden death but not arrhythmia, leaving patients exposed to shocks and device complications affecting quality of life, particularly when young [12]. Substrate ablation altered recurrent VF prognosis: 95% five-year VF-free survival in BRAVO, 96% versus 50% in the single-centre randomised trial, and significant reduction in the multicentre trial [23–25]. These apply to highly symptomatic patients at experienced centres, cannot be transferred to asymptomatic patients and cannot justify dispensing with ICD outside trials. Demonstrated loss-of-function SCN5A carriers have higher lethal event rates (7.9% annually) than all probands (2.5%) [33]. P/LP carriers with negative provocation have excellent arrhythmic prognosis, but more than half develop progressive conduction delay; surveillance then targets bradyarrhythmia requiring pacing [35]. Paediatric rates in the 2026 consensus are 2.1% annually overall, 4.5% in symptomatic patients and zero in asymptomatic patients in one series [6].

12. Summary and Final Considerations

Brugada syndrome is defined by right precordial type 1, spontaneous or sodium blocker-/fever-unmasked, associated with polymorphic VT and VF risk without macroscopic structural heart disease. Since eight patients were described in 1992 and the first SCN5A variant in 1998, three conceptual revisions guide practice. First, diagnosis: only spontaneous type 1 is independently diagnostic; induced patterns require clinical, familial or genetic support because provocation specificity is limited, with false positives in arrhythmogenic cardiomyopathy, myotonic dystrophy, AV nodal re-entry and healthy individuals. Second, genetics: SCN5A is the only definitively valid gene, all others disputed or refuted by ClinGen; approximately 80% of European probands lack identifiable variants, and substantial polygenic architecture includes ancestry-specific variants partly explaining Southeast Asian prevalence. Third, treatment: ICD remains the sole proven sudden death prevention intervention, quinidine is useful but limited by tolerance and availability, and RV outflow tract epicardial ablation now has two small, prematurely stopped randomised trials showing reduced VF recurrence in highly symptomatic patients.

Management rests on measures independent of devices or medicines: prompt fever treatment, BrugadaDrugs avoidance, alcohol limitation, electrolyte correction, perioperative ECG monitoring and immediate care after syncope. Risk stratification should be multiparametric. Prior arrest carries annual risk of 7.7–14.2%; asymptomatic induced-only patterns 0.03%. Between these extremes, device decisions combine symptoms, ECG pattern type and dynamics, conduction markers, inducibility and genotype, recognising 20–30% device complications as relevant in a young population.

Three practical consequences matter for medical genetics. Reports should state gene, versioned transcript (MANE Select NM_000335.5, MANE Plus Clinical NM_001099404.2), normalised HGVS, zygosity, ACMG/AMP classification and technical limitations; disputed/refuted genes should not be reported diagnostically. Historical Nav1.5 numbering differs from MANE Select downstream of residue 1077, so conversions require dedicated database confirmation rather than recall. A VUS does not become pathogenic through partial segregation or treatment response, but calibrated high-throughput functional assays now reclassify a substantial fraction and estimate penetrance by loss-of-function severity, informing rather than replacing clinical decisions.

Current limitations should be explicit. No medicine is authorised for this disease in the USA or EU, and all pharmacological use is off-label; asymptomatic management remains controversial in the sources themselves; available risk scores including PAT await independent validation; anti-Nav1.5 autoantibodies and polygenic scores are promising but clinically unvalidated; and the two questions shaping the next decade—whether ablation can replace ICD and whether high-risk asymptomatic patients benefit from prophylactic ablation—require larger randomised trials.

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