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Classifications

Channelopathy

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Mappings

MONDO

MONDO:0015263 Brugada syndrome

Primary MONDO disease identifier for this Brugada syndrome root entry.

MONDO:0013146 Brugada syndrome 7 Not Yet Curated

MONDO:0013146 is_a the MONDO:0015263 anchor of this entry and is defined as its SCN3B subtype (intersection_of RO:0004003 HGNC:20665). The SCN3B-Brugada association rests on heterologous-expression reports of reduced sodium current without informative segregation data (PMID:20031595, PMID:23257389, PMID:39761910), and was reclassified as disputed by the ClinGen Brugada gene-validity reappraisal (PMID:29959160) — and refuted outright by ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel in December 2025 — on the grounds that the two originally implicated variants occur in the general population at or above the prevalence of the disease, so it is covered here inside the disputed and unresolved non-SCN5A heterogeneity this entry curates rather than as a standalone disease root or as a peer subtype of the definitive SCN5A form. narrowMatch rather than exactMatch because the anchor also subsumes the SCN5A form and the genotype-negative majority stratum that this gene-restricted child term excludes.

MONDO:0012728 Brugada syndrome 2 Not Yet Curated

The GPD1L child term of this entry's anchor. GPD1L was identified by genetic linkage rather than by candidate-gene screening, but the ClinGen Brugada gene-validity reappraisal (PMID:29959160) still classified it as disputed — the linked region was about 24 million base pairs and was not comprehensively sequenced, the reported variant is now seen in about 1 in 5000 individuals in public databases, and no further family has been described since the 2002 seminal report. ClinGen's Brugada Syndrome Gene Curation Expert Panel records the same disputed classification against Brugada syndrome 1. Covered here inside the disputed non-SCN5A heterogeneity this entry curates rather than as a subtype row.

MONDO:0012742 Brugada syndrome 3 Not Yet Curated

The CACNA1C child term. MONDO does not put a `RO:0004003` gene edge on this term directly; it inherits CACNA1C through a second parent, `MONDO:0700321 CACNA1C-related disorder`, which is why a gene-keyed diff over this series does not see it. ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel classified CACNA1C for Brugada syndrome as disputed in 2025, and the earlier reappraisal found segregation in only 2 individuals in 2 generations. The gene's definitive disease, Timothy syndrome, is curated separately in this KB.

MONDO:0012743 Brugada syndrome 4 Not Yet Curated

The CACNB2 child term. CACNB2 is one of only three reported Brugada genes with more than two segregations within a family, but the reappraisal's curators found a reported affected individual in that family who did not carry the variant, and ClinGen's current assertion for CACNB2 — made against the broader `MONDO:0100547 cardiogenetic disease` rather than against Brugada syndrome — is disputed. Covered here rather than as a subtype row.

MONDO:0013015 Brugada syndrome 5 Not Yet Curated

The SCN1B child term. SCN1B is among the 13 genes whose seminal manuscripts reported rare variants in sporadic cases only, with no segregation data and no evidence of rare-variant excess against controls, and ClinGen's Brugada Syndrome Gene Curation Expert Panel classifies it as disputed. Covered here rather than as a subtype row.

MONDO:0013145 Brugada syndrome 6 Not Yet Curated

The KCNE3 child term. KCNE3 is the second of the three genes reported with more than two segregations, but the reappraisal judged those four segregations insufficient without statistical data, further families or other supporting literature, and ClinGen restated the disputed classification in 2025. Covered here rather than as a subtype row.

MONDO:0013148 Brugada syndrome 8 Not Yet Curated

The HCN4 child term. HCN4 is among the 13 genes whose seminal manuscripts reported rare variants in sporadic cases only, with no segregation data and no evidence of rare-variant excess against controls, and ClinGen's Brugada Syndrome Gene Curation Expert Panel classifies it as disputed for Brugada syndrome. HCN4 does carry a separate ClinGen assertion for sick sinus syndrome 2, which is a different disease and not this entry's concern. Covered here rather than as a subtype row.

MONDO:0014621 Brugada syndrome 9 Not Yet Curated

The KCND3 child term. KCND3 is among the 13 genes whose seminal manuscripts reported rare variants in sporadic cases only, with no segregation data and no evidence of rare-variant excess against controls, and ClinGen's Brugada Syndrome Gene Curation Expert Panel classifies it as disputed. Covered here rather than as a subtype row.

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Definitions

1

Fever-associated type-1 Brugada ECG case-finding query for latent SCN5A/Brugada carriers

EHR/OMOP case-finding query: identify individuals in whom a type-1 coved Brugada ECG (or a fever-triggered ventricular arrhythmia) is documented during a febrile episode, as candidates for latent/undiagnosed Brugada syndrome warranting off-fever confirmation and SCN5A evaluation. Contrast with the Timothy fever query: here the fever→unmasking mechanism is established, so derivation_basis is ESTABLISHED_CRITERIA rather than MECHANISTIC_HYPOTHESIS.

PHENOTYPE_ALGORITHM EHR/OMOP case-finding for latent Brugada carriers; grounded in established fever-unmasking biology but not yet validated as a computable phenotype.

Fever-associated type-1 Brugada ECG

A type-1 coved right-precordial ST-segment elevation, or a ventricular tachyarrhythmia, documented during a febrile episode in a patient without a prior Brugada diagnosis; confirm off-fever and refer for SCN5A testing.

Inclusion criteria

Documented febrile episode Elevated body temperature or a febrile-illness diagnosis code (index exposure).
Type-1 Brugada ECG or fever-triggered ventricular arrhythmia Coved type-1 right-precordial ST-segment elevation, or a ventricular tachyarrhythmia, recorded during the febrile episode.

Exclusion criteria

Pre-existing Brugada diagnosis Already-diagnosed Brugada syndrome (not a latent-case-finding hit).

Show evidence (2 references)

PMID:27033637 SUPPORT Human Clinical

"One hundred twelve patients with BrS who developed F-type1 were retrospectively enrolled."

Establishes fever-induced type-1 Brugada ECG as an identifiable clinical cohort — the population this query targets.

PMID:27033637 SUPPORT Human Clinical

"26.4% (14 of 53) carried a pathogenic SCN5A mutation."

A substantial fraction of fever-induced type-1 patients carry a pathogenic SCN5A variant, supporting the case-finding rationale that fever-provoked type-1 ECG enriches for genotype-positive carriers.

Notes: Worked ESTABLISHED-basis counterpart to the Timothy fever_exacerbated_cav1.2 query: same trigger-provoked-latent-disease archetype, but the fever→Nav1.5 unmasking mechanism is settled, so derivation_basis is ESTABLISHED_CRITERIA (validation_status UNVALIDATED for the computable phenotype itself). See docs/hypothesis-based-phenotype-algorithms.md and docs/reports/hypothesis-driven-ehr-case-finding-2026-07-12.md.

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Subtypes

2

Genotype-negative or oligogenic Brugada syndrome

Majority stratum of clinically diagnosed Brugada syndrome in which no single definitive monogenic cause is identified. Current evidence supports a heterogeneous architecture involving unresolved rare variation, common variant burden, and multiple non-SCN5A candidate genes that should not be promoted to standalone disease roots without stronger evidence. Despite the subtype name, no oligogenic inheritance term (HP:0010983) is bound and this entry is not a member of the Digenic and Oligogenic Disorders grouping. The cited evidence establishes that 70-85% of cases are genetically unresolved, which is an absence of a monogenic explanation rather than a demonstration of two or a few co-transmitted loci; a common-variant burden architecture would in any case be polygenic (HP:0010982), not oligogenic. The subtype is retained under its published name because that is how the stratum is labelled in the literature.

Show evidence (3 references)

PMID:32121523 SUPPORT Other

"Although BrS is considered a genetic disease, its molecular mechanism remains elusive in about 70-85% of clinically-confirmed cases."

Establishes that most clinically confirmed Brugada syndrome remains genetically unresolved.

PMID:32121523 SUPPORT Other

"Variants occurring in at least 26 different genes have been previously considered causative, although the causative effect of all but the SCN5A gene has been recently challenged, due to the lack of systematic, evidence-based evaluations, such as a variant's frequency among the general..."

Supports treating non-SCN5A Brugada genes as unresolved or disputed heterogeneity rather than as established monogenic roots.

PMID:20301690 SUPPORT REVIEW SYNTHESIS Human Clinical

"A molecular diagnosis can be established in an individual with characteristic features and identification of a heterozygous pathogenic variant in SCN5A or one of the additional 42 genes associated with Brugada syndrome."

The GeneReviews chapter still lists 42 non-SCN5A genes as diagnostic, which the ClinGen reappraisal cited on this entry's SCN3B record contradicts for 20 of the 21 it curated. Recorded here because the disagreement is between two standard sources rather than between a source and this entry, and it is what this subtype exists to hold.

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Discussions and Knowledge Gaps

3

Can New Approach Methodologies functionally confirm SCN5A carriers surfaced by the fever-associated type-1 ECG case-finding query — using patient iPSC-cardiomyocyte and heterologous Nav1.5 temperature-challenge assays to show temperature-dependent sodium-current loss?

OPEN QUESTION OPEN q_brs_fever_query_nam_confirmation

Attached to

pathophysiology#Fever-induced accentuation of sodium-channel loss of function

The fever→type-1-ECG mechanism is established, but a candidate surfaced by the EHR query still needs functional confirmation that the specific SCN5A variant is temperature-sensitive. A human-relevant New Approach Methodology assay — patient iPSC-cardiomyocytes and heterologous Nav1.5 expression subjected to a temperature ramp — directly measures the temperature-dependent INa loss that underlies fever unmasking, and is the mechanistic complement to the population EHR arm.

Proposed experiments

iPSC-cardiomyocyte and heterologous Nav1.5 temperature-challenge assay

iPSC-cardiomyocyte and heterologous-expression temperature-challenge assay

exp_brs_nav15_temperature_nam

Express the candidate SCN5A variant heterologously and record INa across a temperature ramp (e.g. 32 to 40 degrees C); in parallel, subject patient-derived (and isogenic-corrected) iPSC-cardiomyocytes to the same temperature challenge and assess emergence of a type-1-like depolarization/repolarization phenotype. Temperature-dependent INa loss and phenotype accentuation in the variant but not the control would confirm the fever-sensitive substrate.

Model systems

Heterologous Nav1.5 (SCN5A) expression

Candidate SCN5A variant expressed in a mammalian cell line; INa recorded across a temperature ramp.

CELL LINE

human NCBITaxon:9606

Patient iPSC-derived cardiomyocytes

Patient-derived and isogenic-corrected iPSC-cardiomyocytes challenged with a temperature ramp.

IPSC DERIVED MODEL

human NCBITaxon:9606

Perturbations

Temperature ramp (fever challenge)

pathophysiology#Fever-induced accentuation of sodium-channel loss of function

Raise temperature from ~32 to ~40 degrees C, comparing variant with isogenic control.

Readouts

Temperature-dependent sodium-current loss and arrhythmic phenotype

pathophysiology#Malignant Ventricular Tachyarrhythmia

INa density/gating across temperature, and emergence of type-1-like depolarization abnormalities / arrhythmic activity in cardiomyocytes.

Decision criterion

Temperature-dependent INa loss and type-1-like phenotype accentuation in the candidate SCN5A variant but not the isogenic control.

Supporting outcome

The variant is temperature-sensitive, confirming a fever-query hit as a true SCN5A carrier with a fever-unmaskable substrate.

Refuting outcome

No temperature dependence, indicating the query hit is not explained by that variant.

Do any of the individual reported non-SCN5A Brugada genes, SCN3B among them, have enough segregation or case-excess evidence to move out of the disputed tier, or are they better understood as weak-effect contributors within the oligogenic stratum this entry already models, or as arrhythmia genes whose reported Brugada association does not hold at all?

KNOWLEDGE GAP OPEN gap_brs_nonscn5a_gene_validity

Attached to

pathophysiology#Reduced Depolarization Reserve genetic#SCN3B variants

Twenty of the twenty-one genes curated by the reappraisal are classified as disputed, and the founding reports for most of them, SCN3B included, were sporadic cases without informative segregation data or demonstrated rare-variant excess. That leaves the numbered MONDO series (Brugada syndrome 2 through 9) naming gene-specific entities whose gene-disease claims the field does not currently support. This entry already models the majority stratum as genotype-negative or oligogenic; what remains open is the status of these specific reported genes within it, that is, whether any individual one is a weak-effect contributor or simply not a Brugada gene at all. SCN3B is the concrete test case: its null mouse does produce reduced ventricular sodium current and inducible ventricular tachycardia, yet the specific human alleles reported for it are commoner in the population than the disease is, and one of them was also reported in lone atrial fibrillation. Resolving this determines whether this entry should ever carry gene-specific subtypes beyond SCN5A.

Show evidence (1 reference)

PMID:29959160 SUPPORT Other

"After comprehensive review by the clinical domain Expert panel, all 20 genes classified as limited evidence were reclassified as disputed with regard to any assertions of disease causality for BrS."

Establishes that the disputed classification covers the whole non-SCN5A set rather than SCN3B alone, which is what makes this a stratum-level gap.

The Scn3b-null mouse reproduces the sodium-current and ventricular arrhythmia phenotype, but does complete loss of beta-3 in mouse say anything about the heterozygous human alleles, which are commoner in the population than Brugada syndrome is?

HUMAN MODEL MISMATCH OPEN mismatch_scn3b_null_mouse_atrial_phenotype

Attached to

animal_models#Scn3b-null mouse (Scn3b-/-) genetic#SCN3B variants

The in vivo model and the human genetics point in opposite directions, and the mismatch is at the level of the allele rather than the mechanism. Scn3b-null mice have reduced peak sodium current in ventricular myocytes, shortened ventricular effective refractory periods, and inducible ventricular tachycardia that the authors read as resembling Scn5a heterozygous hearts, so loss of beta-3 plainly can produce a sodium-channel-dependent ventricular arrhythmic substrate. But the model is a homozygous null, while every reported human variant is heterozygous, and two of them occur in the general population at roughly the prevalence of Brugada syndrome itself. So a strong model phenotype coexists with human alleles that cannot carry the disease at the frequency observed. Either the reported missense alleles do not approach the functional severity of a null, or beta-3 loss contributes only as a modifier on other substrate. Which of those holds determines whether the disputed classification is a statement about SCN3B or only about the specific alleles so far reported, and a heterozygous knock-in of the human alleles is the experiment that would separate them. Note that this discussion_id predates the question it now asks: it was first written around an apparent atrial-versus-ventricular mismatch that the Hakim 2008 ventricular data disproved. The id is retained as a stable key and should not be read as the claim.

Show evidence (2 references)

PMID:19351516 SUPPORT Model Organism

"Together, these findings associate the lack of the Scn3b gene with arrhythmic tendencies in intact perfused hearts and electrophysiological features similar to those in Scn5a(+/-) hearts."

Establishes the strong model-side phenotype that makes the contrast with the human allele frequencies a genuine mismatch rather than a simple absence of model support.

PMID:29959160 SUPPORT REVIEW SYNTHESIS Human Clinical

"Two curated genes in this study were originally implicated on the basis of variants suggested to be rare in the original studies, only to be subsequently noted to have heterozygosity frequency in public databases greater than or equal to the prevalence of BrS (KCNJ8 p.Ser422Leu, 1/250; SCN3B..."

The human-side half of the mismatch: the specific reported alleles are too common to cause the disease, whatever the null mouse shows.

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Pathophysiology

6

Reduced Depolarization Reserve

Brugada syndrome converges on reduced depolarizing reserve in ventricular cardiomyocytes, most often through decreased inward sodium current but also through broader ion-current imbalance involving calcium and potassium channel pathways. At the disease level, the key mechanistic theme is not long-QT-like delayed repolarization alone but reduced inward current and impaired conduction reserve in the right ventricular substrate.

cardiomyocyte CL:0000746 right ventricular cardiomyocyte CL:2000046

SCN5A hgnc:10593 ⇓ LOSS OF FUNCTION SCN3B hgnc:20665 ⇓ LOSS OF FUNCTION

membrane depolarization during cardiac muscle cell action potential GO:0086012 ↓ DECREASED cardiac conduction GO:0061337 ↓ DECREASED sodium ion transport GO:0006814 ↓ DECREASED

monoatomic ion channel activity GO:0005216 ⚠ ABNORMAL

outflow tract of right ventricle UBERON:0005953

Animal models

Scn3b-null mouse (Scn3b-/-) Mouse partially recapitulates Complete loss of the beta-3 subunit reduces peak sodium current density measured directly in ventricular myocytes and slows cardiac conduction in vivo, matching the direction of the reduced sodium current that SCN3B variants produce in transfected cells.

Computational models

Subcellular sodium-channel myocardial strand model KINETIC C/Autotools; Intel C Compiler, Intel MKL/PARDISO, and Intel OpenMP (original configuration) The model directly reduces lateral-membrane sodium conductance and measures the resulting action-potential changes, rather than reproducing the full genetically and structurally heterogeneous Brugada mechanism.

Downstream

Type 1 coved ST-segment elevation Reduced depolarization reserve in the right-precordial substrate produces the diagnostic coved ST-segment elevation pattern.

RVOT Conduction Slowing Reduced depolarizing reserve lowers excitation wavelength and promotes localized conduction delay in the right ventricular outflow tract substrate.

Show evidence (2 references)

PMID:33797273 SUPPORT Computational

"Our study suggests that genomic and proteomic hotspots in BrS converge into ion transport pathway and cardiomyocyte as a major BrS-associated cell type that provides insight into the complex genetic etiology of BrS."

Supports ion-transport dysregulation in cardiomyocytes as the convergent disease-level mechanism across genetically heterogeneous Brugada syndrome.

PMID:29024690 SUPPORT In Vitro

"Patient-derived iPS-CM showed a 33.1-45.5% reduction in INa density, a shift in both activation and inactivation voltage-dependence curves, and faster recovery from inactivation."

Directly demonstrates reduced inward sodium current and altered channel gating in a patient-specific SCN5A Brugada cardiomyocyte model.

RVOT Conduction Slowing

Tissue-level Brugada pathophysiology includes delayed depolarization and conduction dispersion in the right ventricular outflow tract, where reduced conduction reserve creates the proximate substrate for malignant ventricular arrhythmia. Heterogeneous, slowed depolarization and conduction across the RVOT constitute the depolarization-predominant arrhythmogenic substrate of Brugada syndrome.

cardiomyocyte CL:0000746 right ventricular cardiomyocyte CL:2000046

cardiac muscle cell action potential GO:0086001 ⚠ ABNORMAL cardiac conduction GO:0061337 ↕ DYSREGULATED

outflow tract of right ventricle UBERON:0005953

Computational models

Subcellular sodium-channel myocardial strand model KINETIC C/Autotools; Intel C Compiler, Intel MKL/PARDISO, and Intel OpenMP (original configuration) Reduced lateral sodium conductance lowers modeled upstroke velocity and strand conduction velocity, recapitulating the conduction-slowing component of the Brugada substrate.

Downstream

Current-Load Mismatch at RVOT Substrate Structural discontinuities in the RVOT coexist with conduction delay and convert reduced conduction reserve into excitation failure and conduction block.

Show evidence (2 references)

PMID:27803673 SUPPORT Other

"These are in keeping with clinical findings of delayed depolarization in the RV outflow tract demonstrated using electroanatomical mapping"

Supports delayed depolarization and conduction slowing in the RV outflow tract as an atomic tissue-level Brugada mechanism.

PMID:27803673 SUPPORT Other

"Decreased λ has been associated with increased likelihood of reentrant arrhythmias"

Supports reduced excitation wavelength from slowed conduction as the tissue-level substrate that raises reentrant ventricular arrhythmia likelihood in Brugada syndrome.

Current-Load Mismatch at RVOT Substrate

Structural abnormalities in the RV and RVOT increase current-to-load mismatch and excitation failure, providing a distinct tissue-level mechanism that can cooperate with conduction slowing to destabilize the Brugada substrate.

cardiomyocyte CL:0000746 right ventricular cardiomyocyte CL:2000046

cardiac muscle cell action potential GO:0086001 ⚠ ABNORMAL cardiac conduction GO:0061337 ↕ DYSREGULATED

outflow tract of right ventricle UBERON:0005953

Downstream

Malignant Ventricular Tachyarrhythmia Excitation failure and conduction block in the RVOT substrate promote reentrant polymorphic VT and VF.

Show evidence (2 references)

PMID:27803673 SUPPORT Other

"In patients with Brugada syndrome, structural abnormalities are indeed observed in the RV and RVOT, which would increase current-load mismatch and excitation failure"

Supports current-to-load mismatch and local excitation failure as a distinct RV/RVOT substrate mechanism in Brugada syndrome.

PMID:27803673 SUPPORT Other

"It was suggested that current-to-load mismatches at discontinuities can cause conduction block."

Supports current-to-load mismatch at structural discontinuities as a mechanistic source of conduction block in the Brugada substrate.

Malignant Ventricular Tachyarrhythmia

The clinical consequence of the Brugada substrate is malignant ventricular tachyarrhythmia, especially polymorphic ventricular tachycardia and ventricular fibrillation, with syncope or sudden cardiac death as the major downstream manifestations.

cardiomyocyte CL:0000746

cardiac conduction GO:0061337 ⚠ ABNORMAL

Animal models

Scn3b-null mouse (Scn3b-/-) Mouse partially recapitulates Beta-3 loss produces an inducible ventricular arrhythmic phenotype with shortened ventricular effective refractory periods, which the authors read as resembling Scn5a heterozygous hearts.

Computational models

Spatially heterogeneous sodium-channel myocardial ring model KINETIC C/Autotools; Intel C Compiler, Intel MKL/PARDISO, and Intel OpenMP (original configuration) The heterogeneous ring produces phase-2-reentry-mediated circulating excitation, representing a reduced tissue-scale mechanism for Brugada reentrant tachyarrhythmia.

Downstream

Polymorphic ventricular tachycardia The Brugada arrhythmogenic substrate can produce polymorphic ventricular tachycardia.

Ventricular fibrillation The Brugada arrhythmogenic substrate can degenerate into ventricular fibrillation.

Syncope and Sudden Cardiac Death Sustained polymorphic ventricular tachycardia or ventricular fibrillation abolishes effective cardiac output, producing syncope and, if not terminated, sudden cardiac death.

Show evidence (2 references)

PMID:39896197 SUPPORT Other

"This condition, identified by Josep and Pedro Brugada, is often marked by symptoms such as syncope and episodes of polymorphic ventricular tachycardia (PVT) or ventricular fibrillation (VF)."

Defines the characteristic malignant ventricular arrhythmias and their clinical presentation in Brugada syndrome.

PMID:39896197 SUPPORT Other

"These arrhythmias, if not managed promptly, can escalate to sudden cardiac death (SCD), notably in patients whose cardiac structure appears normal."

Links Brugada-associated ventricular tachyarrhythmia directly to sudden cardiac death risk.

Syncope and Sudden Cardiac Death

Loss of effective cardiac output from sustained Brugada-associated polymorphic ventricular tachycardia or ventricular fibrillation causes transient cerebral hypoperfusion (syncope) and, when the arrhythmia does not self-terminate, sudden cardiac death. These are the shared clinical endpoints of Brugada syndrome and are frequently the sentinel manifestation in structurally normal hearts.

Downstream

Syncope Syncope is a clinical outcome in Brugada syndrome; the cited cohort classified these events as unexplained and therefore does not establish a documented ventricular tachyarrhythmia for each episode.

Sudden cardiac death Sustained ventricular tachyarrhythmia that does not terminate causes sudden cardiac death.

Show evidence (2 references)

PMID:39896197 SUPPORT Other

"These arrhythmias, if not managed promptly, can escalate to sudden cardiac death (SCD), notably in patients whose cardiac structure appears normal."

Supports syncope/sudden cardiac death as the terminal outcome of Brugada-associated ventricular tachyarrhythmia in structurally normal hearts.

PMID:23499630 SUPPORT Human Clinical

"72 (22%) patients presented with unexplained syncope, and 26 (8%) patients presented with sudden death (12 patients) or appropriated implantable cardioverter-defibrillator therapies (14 patients)"

Human cohort evidence documenting unexplained syncope and sudden death (or appropriate ICD therapy) as the clinical outcomes in Brugada syndrome patients.

Fever-induced accentuation of sodium-channel loss of function

Elevated body temperature accentuates the loss of function of the cardiac sodium channel (Nav1.5/SCN5A) that underlies Brugada syndrome. The Brugada-associated SCN5A mutation Thr1620Met is arrhythmogenic only at temperatures approaching the physiological range, so fever transiently worsens the depolarization-reserve deficit — unmasking or accentuating the diagnostic type-1 coved ST-segment elevation and, in some patients, precipitating malignant ventricular arrhythmia. Unlike the Timothy-syndrome fever effect (an emerging, model-system hypothesis), fever-unmasking of the Brugada ECG is an established clinical phenomenon.

right ventricular cardiomyocyte CL:2000046

SCN5A hgnc:10593

cellular response to heat GO:0034605 ↑ INCREASED

voltage-gated sodium channel activity GO:0005248 ↓ DECREASED

outflow tract of right ventricle UBERON:0005953

Downstream

Type 1 coved ST-segment elevation Fever accentuates sodium-channel loss of function and unmasks or augments the diagnostic type-1 coved ST-segment elevation.

Malignant Ventricular Tachyarrhythmia In some patients fever precipitates fever-triggered malignant ventricular arrhythmia on the accentuated Brugada substrate.

Show evidence (2 references)

PMID:10532948 SUPPORT In Vitro

"illustrate for the first time a cardiac sodium channel mutation of which the arrhythmogenicity is revealed only at temperatures approaching the physiological range, and suggest that some patients may be more at risk during febrile states"

Patch-clamp study of the SCN5A Thr1620Met Brugada mutation shows its arrhythmogenic gating defect emerges near physiological temperature, establishing the temperature-dependence that makes fever an unmasking trigger.

PMID:32015236 SUPPORT Human Clinical

"Fever may not only reveal BrS but also induce life-threatening arrhythmic events, especially in children and adolescents"

Clinical series confirming that fever both unmasks the Brugada pattern and can precipitate malignant arrhythmia.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

5

Type 1 coved ST-segment elevation Cardiovascular HP:6000984

Show evidence (1 reference)

PMID:20233789 SUPPORT Human Clinical

"According to the diagnostic consensus criteria, the electrocardiographic (ECG) diagnosis of Brugada syndrome requires coved-type > or =2 mm ST-segment elevation in >1 right precordial lead (RPL) V1-V3 in the presence or absence of a sodium-channel blocker."

Supports the hallmark diagnostic ECG phenotype for Brugada syndrome.

Syncope Cardiovascular HP:0001279

Show evidence (1 reference)

PMID:23499630 SUPPORT Human Clinical

"Two hundred twenty-five (70%) patients were asymptomatic, 72 (22%) patients presented with unexplained syncope, and 26 (8%) patients presented with sudden death (12 patients) or appropriated implantable cardioverter-defibrillator therapies (14 patients) at diagnosis or over a mean follow-up of..."

Provides cohort-level evidence that syncope is a common presenting manifestation in Brugada syndrome.

Polymorphic ventricular tachycardia Cardiovascular HP:0031677

Show evidence (1 reference)

PMID:39896197 SUPPORT Other

"This condition, identified by Josep and Pedro Brugada, is often marked by symptoms such as syncope and episodes of polymorphic ventricular tachycardia (PVT) or ventricular fibrillation (VF)."

Supports polymorphic ventricular tachycardia as a canonical malignant arrhythmia in Brugada syndrome.

Ventricular fibrillation Cardiovascular HP:0001663

Show evidence (1 reference)

PMID:39896197 SUPPORT Other

"This condition, identified by Josep and Pedro Brugada, is often marked by symptoms such as syncope and episodes of polymorphic ventricular tachycardia (PVT) or ventricular fibrillation (VF)."

Supports ventricular fibrillation as a core malignant arrhythmia phenotype in Brugada syndrome.

Sudden cardiac death Cardiovascular HP:0001645

Show evidence (1 reference)

PMID:39896197 SUPPORT Other

"These arrhythmias, if not managed promptly, can escalate to sudden cardiac death (SCD), notably in patients whose cardiac structure appears normal."

Supports sudden cardiac death as the principal life-threatening outcome of Brugada-associated ventricular arrhythmia.

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Genetic Associations

9

SCN5A loss-of-function variants (Causative)

Gene: SCN5A hgnc:10593 gene page relationship_type: CAUSATIVE

Show evidence (4 references)

PMID:35004896 SUPPORT Other

"However, pathogenic rare variants in SCN5A are identified in only 20-30% of cases, and recent data indicates that SCN5A variants are actually, in many cases, prognostic rather than diagnostic, resulting in a more severe phenotype."

Shows that SCN5A is clinically important but explains only a minority of diagnosed Brugada syndrome, consistent with a root entry plus subtype model.

PMID:33797273 SUPPORT Computational

"We observed an over-representation of clinically relevant mutations (∼80%) in SCN5A gene and also identified several candidate genes, including GPD1L, TRPM4, and SCN10A."

Supports SCN5A as the dominant high-confidence gene within the clinically curated Brugada variant landscape.

CGGV:assertion_9f832392-a92b-408d-8d1a-e2037905fab3-2025-10-08T160000.000Z SUPPORT DIRECT Other

ClinGen's current definitive assertion for SCN5A, and the source for this record's statement that it is made against the gene-named concept MONDO:1010181 rather than against Brugada syndrome.

+ 1 more reference

SCN3B variants (Disputed)

Gene: SCN3B hgnc:20665 relationship_type: DISPUTED

Show evidence (12 references)

PMID:20031595 SUPPORT DIRECT In Vitro

"Coexpression of SCN5A/WT+SCN1B/WT+SCN3B/L10P resulted in an 82.6% decrease in peak sodium current density, accelerated inactivation, slowed reactivation, and a -9.6-mV shift of half-inactivation voltage compared with SCN5A/WT+SCN1B/WT+SCN3B/WT."

The heterologous-expression result that is the entire functional basis for the SCN3B-Brugada association, and the reason the reported mechanism is a reduction in sodium current.

PMID:20031595 SUPPORT DIRECT Human Clinical

"A missense mutation (L10P) was detected in exon 1 of SCN3B, the beta 3 subunit of the cardiac sodium channel, but not in any other gene known to be associated with Brugada syndrome or in 296 controls."

Establishes the human observation behind the association: a single proband carrying L10P, absent from 296 controls.

PMID:29959160 REFUTE DIRECT Other

"Seminal manuscripts for 13 of the 19 genes reported rare variants in only sporadic cases with no segregation data or evidence of rare variant excess compared with control subjects (ABCC9, ANK2, CACNA2D1, HCN4, KCND3, KCNH2, KCNJ8, RANGRF, SCN1B, SCN2B, SCN3B, SLMAP, TRPM4)."

Names SCN3B directly among the genes whose founding reports lacked segregation data or rare-variant excess, which is the specific basis for the disputed classification here.

+ 9 more references

GPD1L variants (Disputed)

Gene: GPD1L hgnc:28956 relationship_type: DISPUTED

Show evidence (5 references)

PMID:29959160 REFUTE DIRECT Other

"Notably, the GPD1L gene received limited evidence classification by all 3 curator teams and a final classification of disputed, despite its identification through the use of genetic linkage."

The expert-panel verdict on GPD1L, and the observation that it holds even though this gene was found by linkage rather than by candidate-gene screening.

PMID:29959160 REFUTE DIRECT REVIEW SYNTHESIS Human Clinical

"the observation that the reported variant in this gene is now recognized to be present in 1/5000 individuals in public databases"

The population-frequency argument against the reported GPD1L allele, the same kind of argument that undercut the SCN3B alleles.

PMID:29959160 REFUTE DIRECT Other

"curators and the expert panel noted the extensive size of the linked genomic region, the select sequencing of only a limited number of genes within this large region"

The specific methodological objection to the GPD1L linkage result: the linked interval was large and was not comprehensively sequenced, so an alternative causal gene inside it was never excluded.

+ 2 more references

CACNA1C variants (Disputed)

Gene: CACNA1C hgnc:1390 gene page relationship_type: DISPUTED

Show evidence (2 references)

PMID:29959160 REFUTE DIRECT Other

"Three genes were reported with limited segregation in only 2 individuals in 2 generations (CACNA1C, KCNE5, and SCN10A)."

Names CACNA1C among the genes whose founding Brugada reports showed segregation in only two individuals, the specific basis for the disputed classification.

CGGV:assertion_0d869dbe-c00c-4875-93c8-80ba0436b895-2025-02-25T010000.000Z REFUTE DIRECT Other

ClinGen's current gene-disease validity assertion for CACNA1C against Brugada syndrome, made under SOP11 and dated 2025.

CACNB2 variants (Disputed)

Gene: CACNB2 hgnc:1402 gene page relationship_type: DISPUTED

Show evidence (3 references)

PMID:29959160 SUPPORT INDIRECT Other

"Only 3 genes (CACNB2, KCNE3, PKP2) were reported to have >2 segregations within a family."

Records that CACNB2's founding report carried more segregations than most disputed Brugada genes, which is the reason its disposition needs the specific refutation quoted below rather than the generic one.

PMID:29959160 REFUTE DIRECT REVIEW SYNTHESIS Human Clinical

"our curators noted a reported affected individual who did not carry the reported variant in CACNB2."

The specific segregation failure in the founding CACNB2 family: an affected individual without the variant.

CGGV:assertion_1dd59b42-2ed6-4685-b93b-39ba49ece50b-2025-07-22T160000.000Z REFUTE INDIRECT Other

ClinGen's current CACNB2 assertion. Graded INDIRECT because it is made against the broad cardiogenetic-disease concept rather than against Brugada syndrome specifically, so it bears on the Brugada claim by inclusion rather than directly.

SCN1B variants (Disputed)

Gene: SCN1B hgnc:10586 gene page relationship_type: DISPUTED

Show evidence (2 references)

PMID:29959160 REFUTE DIRECT Other

"Seminal manuscripts for 13 of the 19 genes reported rare variants in only sporadic cases with no segregation data or evidence of rare variant excess compared with control subjects (ABCC9, ANK2, CACNA2D1, HCN4, KCND3, KCNH2, KCNJ8, RANGRF, SCN1B, SCN2B, SCN3B, SLMAP, TRPM4)."

Names SCN1B among the genes whose founding reports lacked segregation data or rare-variant excess, which is the specific basis for the disputed classification here.

PMID:29959160 REFUTE DIRECT Other

"All other genes (20 of 21) received a final classification of disputed with regard to assertions toward causality for BrS by a clinical domain expert panel."

The expert-panel verdict that places SCN1B, along with every other reported non-SCN5A Brugada gene, in the disputed tier.

KCNE3 variants (Disputed)

Gene: KCNE3 hgnc:6243 relationship_type: DISPUTED

Show evidence (2 references)

PMID:29959160 REFUTE DIRECT Other

"Similarly, 4 and 3 segregations were reported in original manuscripts using preconceived candidate gene approaches implicating KCNE3 and PKP2, respectively, but without sufficient statistical data, additional families or supporting evidence in the literature."

Gives the exact reason the KCNE3 claim failed despite four reported segregations: no statistical data, no further families, no supporting literature.

CGGV:assertion_733a6f42-add7-434a-9d4f-a8f11c11c41a-2025-07-22T190000.000Z REFUTE DIRECT Other

ClinGen's current gene-disease validity assertion for KCNE3 against Brugada syndrome, made under SOP11 and dated 2025.

HCN4 variants (Disputed)

Gene: HCN4 hgnc:16882 gene page relationship_type: DISPUTED

Show evidence (2 references)

PMID:29959160 REFUTE DIRECT Other

"Seminal manuscripts for 13 of the 19 genes reported rare variants in only sporadic cases with no segregation data or evidence of rare variant excess compared with control subjects (ABCC9, ANK2, CACNA2D1, HCN4, KCND3, KCNH2, KCNJ8, RANGRF, SCN1B, SCN2B, SCN3B, SLMAP, TRPM4)."

Names HCN4 among the genes whose founding reports lacked segregation data or rare-variant excess, which is the specific basis for the disputed classification here.

PMID:29959160 REFUTE DIRECT Other

"All other genes (20 of 21) received a final classification of disputed with regard to assertions toward causality for BrS by a clinical domain expert panel."

The expert-panel verdict that places HCN4, along with every other reported non-SCN5A Brugada gene, in the disputed tier.

KCND3 variants (Disputed)

Gene: KCND3 hgnc:6239 gene page relationship_type: DISPUTED

Show evidence (2 references)

PMID:29959160 REFUTE DIRECT Other

"Seminal manuscripts for 13 of the 19 genes reported rare variants in only sporadic cases with no segregation data or evidence of rare variant excess compared with control subjects (ABCC9, ANK2, CACNA2D1, HCN4, KCND3, KCNH2, KCNJ8, RANGRF, SCN1B, SCN2B, SCN3B, SLMAP, TRPM4)."

Names KCND3 among the genes whose founding reports lacked segregation data or rare-variant excess, which is the specific basis for the disputed classification here.

PMID:29959160 REFUTE DIRECT Other

"All other genes (20 of 21) received a final classification of disputed with regard to assertions toward causality for BrS by a clinical domain expert panel."

The expert-panel verdict that places KCND3, along with every other reported non-SCN5A Brugada gene, in the disputed tier.

💊

Medical Actions

3

Implantable cardioverter-defibrillator placement

Action: implantable cardioverter-defibrillator placement Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

Device therapy for prevention of sudden cardiac death in high-risk Brugada syndrome, especially after malignant ventricular arrhythmia, syncope with high-risk features, or recurrent ventricular fibrillation.

Mechanism Target:

MODULATES Malignant Ventricular Tachyarrhythmia — ICDs detect and terminate ventricular fibrillation and polymorphic ventricular tachycardia with defibrillation shocks, preventing sudden cardiac death without altering the underlying arrhythmogenic substrate.

Show evidence (1 reference)

PMID:39800093 SUPPORT Human Clinical

"Although implantable cardioverter-defibrillators (ICDs) and quinidine are primary treatments, recurrent BrS-triggered ventricular arrhythmias can persist."

The meta-analysis identifies ICDs as primary treatment for Brugada-triggered ventricular arrhythmias; the cached abstract does not describe the device's detection-and-shock mechanism.

Show evidence (1 reference)

PMID:39800093 SUPPORT Human Clinical

"Although implantable cardioverter-defibrillators (ICDs) and quinidine are primary treatments, recurrent BrS-triggered ventricular arrhythmias can persist."

Supports ICD placement as a primary established treatment in symptomatic or high-risk Brugada syndrome.

Quinidine

Action: Pharmacotherapy NCIT:C15986

Agent: quinidine CHEBI:28593

Quinidine is used as antiarrhythmic pharmacotherapy for suppression of recurrent ventricular arrhythmia and electrical storm in Brugada syndrome, particularly when ICD therapy alone is insufficient or when ablation is not immediately available.

Mechanism Target:

MODULATES Reduced Depolarization Reserve — Quinidine blocks the transient outward potassium current (Ito) in epicardial RVOT cardiomyocytes, partially restoring the balance between inward and outward currents and reducing the action potential notch that precipitates phase-2 reentry.

Show evidence (1 reference)

PMID:27803673 SUPPORT Other

"Thus, either reduced Ito or increased ICa could compensate for the reduced sodium current, in turn reducing the degree of ST segment elevation."

The mechanistic review supports reduced Ito as compensation for reduced sodium current. Together with the treatment-level quinidine evidence, this partially supports the inferred Ito-blocking mechanism.

Show evidence (1 reference)

PMID:40750064 SUPPORT Other

"Paradoxically, this decline in use occurred alongside accumulating evidence supporting quinidine's therapeutic benefit in managing rare, life-threatening ventricular arrhythmias occurring in patients with no organic heart disease (Idiopathic ventricular fibrillation, Brugada syndrome, Early..."

Supports quinidine as a specifically recognized antiarrhythmic option for Brugada syndrome and related idiopathic ventricular fibrillation syndromes.

Epicardial substrate ablation

Action: epicardial ablation Ontology label: Epicardial Ablation NCIT:C157843

Epicardial ablation of the Brugada arrhythmogenic substrate is an increasingly used option for symptomatic patients with recurrent BrS-triggered ventricular arrhythmias despite ICD therapy and/or quinidine.

Mechanism Target:

MODULATES Current-Load Mismatch at RVOT Substrate — Epicardial ablation destroys the fibrotic-fatty RVOT epicardial substrate responsible for abnormal conduction and the current-load mismatch that sustains phase-2 reentry, eliminating the anatomic basis for arrhythmia inducibility.

Show evidence (1 reference)

PMID:39800093 SUPPORT Human Clinical

"In this setting, epicardial substrate ablation has emerged as a promising alternative for symptomatic patients."

The meta-analysis supports epicardial substrate ablation in symptomatic Brugada syndrome, but its abstract does not isolate elimination of the current-load-mismatch substrate as the operative mechanism.

Show evidence (2 references)

PMID:39800093 SUPPORT Human Clinical

"Although implantable cardioverter-defibrillators (ICDs) and quinidine are primary treatments, recurrent BrS-triggered ventricular arrhythmias can persist. In this setting, epicardial substrate ablation has emerged as a promising alternative for symptomatic patients."

Supports epicardial substrate ablation as a treatment option for symptomatic patients with recurrent arrhythmias despite standard therapy.

PMID:39800093 SUPPORT Human Clinical

"Pooled analysis demonstrated resolution of the type 1 pattern in 91% of the cases"

Supports mechanistic and electrocardiographic efficacy of epicardial substrate ablation in symptomatic Brugada syndrome cohorts.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Brugada syndrome:

Brugada phenocopy

Overlapping Features A type 1 or type 2 Brugada ECG pattern in the right precordial leads that is produced by an identifiable, reversible clinical condition in a person who does not have congenital Brugada syndrome. Reported provoking conditions include hyperkalemia and other electrolyte or metabolic derangements (hyponatremia, hypokalemia, acidosis), myocardial ischemia and acute coronary occlusion, pulmonary embolism, mechanical compression of the right ventricular outflow tract (including pectus excavatum), acute pericarditis, septic shock, adjacent pleural-space infection, recreational-drug intoxication, and inappropriate ECG filter settings. The term itself was coined for the acquired Brugada-like pattern of propofol infusion syndrome (curated separately as Propofol_Infusion_Syndrome), yet the classification that adopted the term lists propofol among the sodium-channel-blocking drugs it says mostly cannot be considered phenocopies, so whether that syndrome's ECG change is a phenocopy is unsettled. The ECG pattern itself does not separate the two: in a blinded study, international Brugada experts classified phenocopy and syndrome tracings only marginally better than chance. The distinction matters for management, because a phenocopy resolves when its cause is corrected and does not warrant the long-term risk stratification, drug restrictions or defibrillator decisions that follow a diagnosis of Brugada syndrome.

Distinguishing Features

An identifiable reversible provoking condition present when the pattern is recorded (for example serum potassium above about 6.5 mmol/L in hyperkalemia-induced phenocopy)
Resolution of the Brugada ECG pattern once the provoking condition is corrected, typically within hours for hyperkalemia
A negative provocative challenge with a sodium channel blocker (ajmaline, procainamide or flecainide) after the provoking condition has resolved; this is a mandatory criterion for a class A phenocopy
Absence of a pathogenic variant in Brugada syndrome genes, with the caveat that most clinically confirmed Brugada syndrome is itself genotype-negative, so a negative test supports but does not establish a phenocopy
Absence of a family history of sudden cardiac death; a ventricular arrhythmia at presentation does not exclude a phenocopy, since a class Ic overdose case reported as a drug-induced phenocopy presented with ventricular fibrillation

Show evidence (25 references)

PMID:23094876 SUPPORT PRIMARY RESULT Other

"The term Brugada phenocopy is proposed to describe conditions that induce Brugada-like ECG manifestations in patients without true Brugada syndrome."

The founding definition of the term, which frames the phenocopy as a differential of the syndrome rather than a form of it.

PMID:23094876 SUPPORT BACKGROUND Other

"Riera et al. introduced the term "Brugada phenocopy" to describe an acquired Brugada-like ECG pattern in the setting of propofol infusion syndrome."

Records that the phenocopy term originated with propofol infusion syndrome, crediting the earlier paper that coined it.

PMID:20544610 SUPPORT REVIEW SYNTHESIS Other

"This anesthetic drug may cause a rare condition named propofol infusion syndrome, characterized by unexplained lactic acidosis, lipemia, rhabdomyolysis, cardiovascular collapse and Brugada-like electrocardiographic pattern or Brugada electrocardiographic phenocopy changes following high-dose..."

The paper that introduced the term, describing the Brugada-like pattern as one feature of propofol infusion syndrome after high-dose, prolonged infusion.

+ 22 more references

📊

Related Datasets

6

A rare non-coding enhancer variant in SCN5A contributes to the high prevalence of Brugada syndrome in Thailand geo:GSE264359

Brugada syndrome (BrS) is a cardiac arrhythmia disorder that causes sudden death in young adults. Rare genetic variants in the SCN5A gene, encoding the Nav1.5 sodium channel, and common non-coding variants at this locus, are robustly associated with the condition. BrS is particularly prevalent in Southeast Asia but the underlying ancestry-specific factors remain largely unknown. Methods: Genome sequencing of BrS probands and population-matched controls from Thailand was performed to identify rare non-coding variants at the SCN5A-SCN10A locus that were enriched in BrS cases.

human BULK RNA SEQ n=8

PMID:39391988

Identified by GEO DataSets index search for Brugada syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

N-Palmitoylglycine activates transient receptor potential channel 5 and increases the risk of Brugada syndrome geo:GSE278421

Brugada syndrome (BrS) is an arrhythmic disorder associated with an increased risk of sudden cardiac death; however, current treatment options are limited due to their side effects and variable efficacy. In this study, we employed Mendelian randomization analysis utilizing proteomic, transcriptomic, and metabolomic data to identify potential therapeutic targets for BrS. Our findings indicate that N-palmitoylglycine (PalGly) is linked to an increased risk of BrS and interacts with BrS-associated proteins, demonstrating moderate binding affinities for proteins such as DCC, CR1, CTSB, NAAA, DEFB1, EPHA1, IGF1/IGFBP3/ALS, and LTA.

rat BULK RNA SEQ n=10

PMID:41315851

Identified by GEO DataSets index search for Brugada syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Illumina SNP array data for Brugdata syndrome patients in Taiwan geo:GSE46348

Background Brugada syndrome (BrS) is a rare inherited disease causing sudden cardiac death (SCD). Copy number variants (CNVs) can contribute to disease susceptibility, but their role in Brugada syndrome (BrS) is unknown. We aimed to identify a CNV associated with BrS and elucidated its clinical implications. Methods We enrolled 335 unrelated BrS patients from 2000 to 2018 in the Taiwanese population. Microarray and exome sequencing were used for discovery phase whereas Sanger sequencing was used for the validation phase. HEK cells and zebrafish were used to characterize the function of the CNV variant.

human GWAS n=16

PMID:32645615

Identified by GEO DataSets index search for Brugada syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Brugada Syndrome-associated Genetic Loci are associated with J-point Elevation and an Increased Risk of Cardiac Arrest ega:EGAS00001003059

Introduction: A previous genome-wide association study found three genetic loci, rs9388451, rs10428132, and rs11708996, toincrease the risk of Brugada Syndrome (BrS). Since the effect of these loci in the general population is unknown, we aimed toinvestigate the effect on electrocardiogram (ECG) parameters and outcomes in the general population.Material and Methods: A cohort of 6,161 individuals (median age 45 [interquartile range (IQR) 40-50] years, 49% males), withavailable digital ECGs, was genotyped and subsequently followed for a median period of 13 [IQR 12.6-13.4] years. Data on outcomeswere collected from Danish administrative healthcare registries.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Brugada syndrome"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Short and long-read sequencing of Brugada syndrome samples ega:EGAS00001004927

Genome-wide association studies (GWAS) are instrumental in identifying loci with an impact on human traits and disease. Typically, however, most GWAS information is considered redundant as it is based on neighboring single-nucleotide variants (SNVs) in strong linkage disequilibrium (LD). In this context, besides the most significant hit (lead SNV) in every trait- or disease-associated locus, the rest of GWAS hits are often marginally reported, examined, or exploited.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Brugada syndrome"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Searching for genetic modulators of the phenotypic heterogeneity in Brugada Syndrome ega:EGAS00001005848

human WES

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Brugada syndrome"); description-level mentions were not accepted. EGA study_type: Exome Sequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

🐁

Animal Models

1

Scn3b-null mouse (Scn3b-/-)

Germline Scn3b knockout mouse, the only in vivo model of the gene behind Brugada syndrome 7. Scn3b transcript is absent from the atria and the beta-3 protein from cardiac myocytes, while Scn1b and Scn5a transcript levels are unchanged, so the phenotype is attributable to loss of beta-3 specifically. The reported cardiac phenotype spans both chambers, in two papers from the same group: sinus bradycardia, P-wave and PR prolongation, prolonged sinus node recovery, atrioventricular dissociation and inducible atrial tachyarrhythmia, and separately reduced peak sodium current in ventricular myocytes with shortened ventricular effective refractory periods and inducible monomorphic or polymorphic ventricular tachycardia.

Species

Mouse

Genotype

Scn3b homozygous knockout

Genes

SCN3B hgnc:20665

Publication

PMID:19796257

Pathograph links

Reduced Depolarization Reserve partially recapitulates fidelity: moderate Complete loss of the beta-3 subunit reduces peak sodium current density measured directly in ventricular myocytes and slows cardiac conduction in vivo, matching the direction of the reduced sodium current that SCN3B variants produce in transfected cells.

Limitations: The model is a homozygous null, whereas the reported human variants are heterozygous missense or single-codon deletions, so it speaks to complete loss of beta-3 rather than to the alleles actually found in patients, and those alleles are what the disputed classification turns on. Murine ventricular repolarization also differs substantially from human, the standing caveat for any mouse model of a repolarization-dependent arrhythmia syndrome.

Readouts

Atrioventricular conduction time (PR interval)

Direction: INCREASED

Interpretation: PR prolongation is the in vivo correlate of reduced sodium-channel availability, the same direction of effect reported for SCN3B variants in heterologous expression.

Show evidence (1 reference)

PMID:19796257 SUPPORT Model Organism

"Lead I electrocardiograms from Scn3b(-/-) mice showed slower heart rates, longer P wave durations and prolonged PR intervals than WT hearts."

Reports the conduction measurements behind this readout.

Atrial arrhythmia inducibility on burst pacing

Direction: INCREASED

Interpretation: Inducible atrial tachyarrhythmia is the arrhythmic counterpart of reduced sodium-channel availability in this chamber; the companion study reports the ventricular counterpart separately.

Show evidence (1 reference)

PMID:19796257 SUPPORT Model Organism

"Atrial burst pacing protocols induced atrial tachycardia and fibrillation in all Scn3b(-/-) but hardly any WT hearts."

Reports the inducible atrial arrhythmia behind this readout.

Show evidence (2 references)

PMID:19796257 SUPPORT Model Organism

"These findings demonstrate, for the first time, that a deficiency in Scn3b results in significant atrial electrophysiological and intracardiac conduction abnormalities, complementing the changes in ventricular electrophysiology reported on an earlier occasion."

Supports treating the model as informative for the depolarization-reserve node, and points to the companion ventricular study.

+ 1 more reference

Malignant Ventricular Tachyarrhythmia partially recapitulates fidelity: moderate Beta-3 loss produces an inducible ventricular arrhythmic phenotype with shortened ventricular effective refractory periods, which the authors read as resembling Scn5a heterozygous hearts.

Limitations: The arrhythmia is induced by programmed electrical stimulation in a Langendorff-perfused heart rather than arising spontaneously, and it is not reported as arising from a right-ventricular outflow-tract substrate with the epicardial repolarization heterogeneity that characterises human Brugada syndrome. As above, the genotype is a homozygous null rather than the heterozygous human alleles.

Readouts

Inducible ventricular tachycardia on programmed stimulation

Direction: INCREASED

Interpretation: Establishes that loss of beta-3 alone is sufficient for ventricular arrhythmic vulnerability in an intact heart.

Show evidence (1 reference)

PMID:19351516 SUPPORT Model Organism

"Bipolar electrogram and monophasic action potential recordings from the ventricles of Langendorff-perfused Scn3b(-/-) hearts demonstrated significantly shorter ventricular effective refractory periods (VERPs), larger ratios of electrogram duration obtained at the shortest and longest S(1)-S(2)..."

Reports the inducible ventricular tachycardia behind this readout.

Show evidence (1 reference)

PMID:19351516 SUPPORT Model Organism

"Together, these findings associate the lack of the Scn3b gene with arrhythmic tendencies in intact perfused hearts and electrophysiological features similar to those in Scn5a(+/-) hearts."

Supports treating the model as informative for the ventricular arrhythmia node, by explicit comparison with the canonical sodium-channel arrhythmia model.

Show evidence (1 reference)

PMID:19796257 SUPPORT Model Organism

"Scn3b mRNA was expressed in the atria of WT but not Scn3b(-/-) hearts."

Confirms the model is a true null for the gene of interest, which is what makes it informative about the consequences of losing beta-3.

🧮

Computational Models

2

Subcellular sodium-channel myocardial strand model C source, Autotools build files, and positional text input C/Autotools; Intel C Compiler, Intel MKL/PARDISO, and Intel OpenMP (original configuration) KINETIC

A one-dimensional strand of 300 human epicardial ventricular myocytes for studying how subcellular sodium-channel distribution changes action-potential morphology and propagation. Each cell is divided into lateral and pre- and post-junctional membrane segments, represented by a modified O'Hara-Rudy dynamic model with ten Tusscher-Panfilov fast sodium current and an experimentally based rapid delayed-rectifier potassium current. Cells are coupled through gap junctions and ephaptic interactions. The disease-like manipulation reduces lateral-membrane sodium conductance while retaining junctional sodium conductance.

Repository ↗ PMID:33203944 Base model: Modified O'Hara-Rudy dynamic 2011 human ventricular model with ten Tusscher-Panfilov fast INa and experimental IKr

Variable	Model ID	Unit	Ontology Mappings	Phenotype Thresholds
Lateral-membrane sodium conductance fraction Fast and late lateral-membrane sodium conductance expressed as a percentage of control.
Action-potential membrane voltage Membrane-potential trajectory for each modeled cell and membrane segment.
Conduction velocity Propagation velocity along the myocardial strand in centimeters per second, derived in the publication from activation-time outputs rather than emitted directly by the code.

Pathograph links

Reduced Depolarization Reserve perturbs fidelity: moderate The model directly reduces lateral-membrane sodium conductance and measures the resulting action-potential changes, rather than reproducing the full genetically and structurally heterogeneous Brugada mechanism.

Limitations: Sodium-channel reduction is prescribed phenomenologically rather than generated by an SCN5A allele, trafficking defect, or patient-calibrated expression state. The model does not represent broader calcium- or potassium-channel causes of reduced depolarization reserve.

Readouts

Action-potential dome morphology

Progressive lateral sodium-channel reduction produces notch-and-dome, delayed-dome, and loss-of-dome action potentials.

Direction: ALTERED

Show evidence (1 reference)

PMID:33203944 SUPPORT Computational

"Reducing Na+ channel expression in the lateral membrane of each myocyte caused not only the notch-and-dome but also loss-of-dome type action potentials and slowed conduction, both of which are typically observed in BrS patients."

The strand simulation reports the expected action-potential response to its sodium-conductance perturbation.

Show evidence (1 reference)

PMID:33203944 SUPPORT Computational

"Reducing Na+ channel expression in the lateral membrane of each myocyte caused not only the notch-and-dome but also loss-of-dome type action potentials and slowed conduction, both of which are typically observed in BrS patients."

The paper identifies the manipulated sodium-channel process and its electrophysiologic outputs.

RVOT Conduction Slowing partially recapitulates fidelity: moderate Reduced lateral sodium conductance lowers modeled upstroke velocity and strand conduction velocity, recapitulating the conduction-slowing component of the Brugada substrate.

Limitations: This is a homogeneous one-dimensional generic epicardial ventricular strand, not an anatomically reconstructed RVOT. It omits patient-specific geometry, fibrosis, fiber organization, ECG leads, and clinical conduction maps.

Readouts

Conduction velocity

Conduction velocity falls as lateral-membrane sodium conductance is reduced from control to complete loss.

Direction: DECREASED

Show evidence (1 reference)

PMID:33203944 SUPPORT Computational

"CVs at 100%gNa,LM, 35%gNa,LM, 7%gNa,LM and 0%gNa,LM were 71.4, 53.6, 33.3, and 25.0 cm/s, respectively (see Table 1)."

The full-text figure caption provides the quantitative conduction-velocity response.

Show evidence (1 reference)

PMID:33203944 SUPPORT Computational

"Reducing Na+ channel expression in the lateral membrane of each myocyte caused not only the notch-and-dome but also loss-of-dome type action potentials and slowed conduction, both of which are typically observed in BrS patients."

The primary report directly identifies slowed propagation as a model output.

Findings

In the homogeneous-conductance comparison, reducing lateral-membrane sodium conductance from 100% to 0% lowers conduction velocity from 71.4 to 25.0 cm/s.

Show evidence (1 reference)

PMID:33203944 SUPPORT Computational

"CVs at 100%gNa,LM, 35%gNa,LM, 7%gNa,LM and 0%gNa,LM were 71.4, 53.6, 33.3, and 25.0 cm/s, respectively (see Table 1)."

The paper reports a monotonic decrease across its four homogeneous conductance settings.

Notes

The repository is pinned at commit 90962d4c159d5b12133d99cb0818c84c6746a013 and has no release, CI, container, or dependency lock. COPYING declares GPL-3.0, but src/pardiso_mat.c carries an Intel Confidential notice that restricts use, copying, and distribution; the effective reuse and redistribution status is therefore ambiguous. The checked-in build targets legacy Intel C Compiler, MKL/PARDISO, and OpenMP paths and flags. It did not compile unmodified during curator testing on ARM macOS. The fixed-step explicit-Euler simulation uses a 1-microsecond step for 30 beats. Its only sample input is stale: for the supplied one-dataset, 43-state configuration, the parser reads 83 numeric fields whereas check_test/in supplies 82, shifting later values and preventing a faithful run. No paper-scenario manifest, expected outputs, or automated tests are supplied. The code emits voltage and ionic traces plus activation times but does not directly calculate CV; nai_data.out and ki_data.out are also mislabeled relative to their written state indices. The article is CC BY 4.0. The model was compared qualitatively with prior mouse and human electrophysiology, but it was not fitted to or independently validated in a Brugada patient cohort.

Show evidence (1 reference)

PMID:33203944 SUPPORT Computational

"We constructed in silico human ventricular myocardial strand and ring models, and examined whether the Na+ channel expression changes in each myocyte cause the phase-2 reentry in BrS."

The publication defines the human ventricular strand model and its Brugada perturbation.

Spatially heterogeneous sodium-channel myocardial ring model C source, Autotools build files, and positional text input C/Autotools; Intel C Compiler, Intel MKL/PARDISO, and Intel OpenMP (original configuration) KINETIC

A one-dimensional ring of 600 human epicardial ventricular myocytes using the same modified O'Hara-Rudy ionic model, segmented cell membranes, gap junctions, and ephaptic coupling as the companion strand model. Two ring regions are assigned different, markedly reduced lateral-membrane sodium conductances to test whether spatial heterogeneity converts phase-2 reentry into intermittent or persistent circulating reentrant excitation.

Repository ↗ PMID:33203944 Base model: Modified O'Hara-Rudy dynamic 2011 human ventricular model with ten Tusscher-Panfilov fast INa and experimental IKr

Variable	Model ID	Unit	Ontology Mappings	Phenotype Thresholds
Regional lateral-membrane sodium conductance fractions Separately imposed percentages of control lateral sodium conductance in the two ring regions.
Action-potential propagation pattern Spatiotemporal membrane-voltage propagation around the ring; block, phase-2 reentry, and circulating reentry are interpreted from the traces rather than classified directly by the code.

Pathograph links

Malignant Ventricular Tachyarrhythmia partially recapitulates fidelity: low The heterogeneous ring produces phase-2-reentry-mediated circulating excitation, representing a reduced tissue-scale mechanism for Brugada reentrant tachyarrhythmia.

Limitations: The 600-cell one-dimensional ring is not an RVOT or whole-heart geometry and cannot reproduce polymorphic VT, ventricular fibrillation, surface ECG, hemodynamics, or patient outcomes. Reentry depends on imposed and locally extreme sodium-conductance heterogeneity rather than measured patient tissue or a disease genotype.

Readouts

Phase-2-reentry-mediated reentrant arrhythmia

Spatially heterogeneous lateral sodium-channel reduction produces intermittent or persistent unidirectional circulating excitation.

Direction: INCREASED

Show evidence (1 reference)

PMID:33203944 SUPPORT Computational

"Furthermore, the selective reduction in Na+ channels on the lateral membrane of each myocyte together with spatial tissue heterogeneity of Na+ channel expression caused the phase-2 reentry and phase-2 reentry-mediated reentrant arrhythmias."

The ring simulation directly produces its reduced reentrant-arrhythmia readout.

Show evidence (1 reference)

PMID:33203944 SUPPORT Computational

"Furthermore, the selective reduction in Na+ channels on the lateral membrane of each myocyte together with spatial tissue heterogeneity of Na+ channel expression caused the phase-2 reentry and phase-2 reentry-mediated reentrant arrhythmias."

The publication identifies sodium-channel heterogeneity as necessary for the modeled reentry.

Findings

Reentry occurred mainly when region B lateral sodium conductance was below 5% of control and region A was between 5% and 10%, underscoring dependence on an extreme imposed spatial gradient.

Show evidence (1 reference)

PMID:33203944 SUPPORT Computational

"This result indicates that the P2R-mediated reentry occurred mostly when the %gNa,LM in the region B was reduced to < 5% and the %gNa,LM in the region A was in the 5 ~ 10% range (Fig. 6C, magenta region)."

The phase diagram identifies the parameter region supporting ring reentry.

Notes

The repository is pinned at commit 0a6aece22925ca48430d775589547bbfbf9e0ff0 and has no release, CI, container, dependency lock, or sample input. COPYING declares GPL-3.0, but src/pardiso_mat.c carries an Intel Confidential notice that restricts use, copying, and distribution; the effective reuse and redistribution status is therefore ambiguous. The checked-in build targets legacy Intel C Compiler, MKL/PARDISO, and OpenMP paths and flags and did not compile unmodified during curator testing on ARM macOS. The fixed-step explicit-Euler simulation uses a 1-microsecond step for 30 beats, nominally 30 million steps. The repository supplies no paper-figure parameter manifest, golden output, analysis script, or automated test. It emits voltage and current traces but does not directly label phase-2 reentry, reentrant arrhythmia, or the published phase diagram; an auxiliary cleft-potential output also omits the closing ring junction. The article is CC BY 4.0. This is a hypothesis-driven mechanism model, not an allele-specific, anatomically personalized, or clinically predictive ventricular simulation.

Show evidence (1 reference)

PMID:33203944 SUPPORT Computational

"We constructed in silico human ventricular myocardial strand and ring models, and examined whether the Na+ channel expression changes in each myocyte cause the phase-2 reentry in BrS."

The publication defines the human ventricular ring model and its Brugada perturbation.

{ }

Source YAML

click to show

name: Brugada syndrome
creation_date: '2026-04-14T00:00:00Z'
description: >-
  Brugada syndrome is an inherited cardiac channelopathy and primary electrical
  disease characterized by a type 1 coved ST-segment elevation in the right
  precordial leads together with risk of polymorphic ventricular tachycardia,
  ventricular fibrillation, syncope, and sudden cardiac death in structurally
  normal hearts. This entry treats Brugada syndrome as the inherited arrhythmia
  root rather than mirroring long QT syndrome subtype framing. SCN5A-related
  Brugada syndrome is the best-supported monogenic subtype, whereas most
  clinically confirmed cases remain genotype-negative or genetically unresolved
  and many reported non-SCN5A genes remain candidate or disputed.
synonyms:
- BrS
category: Genetic
disease_term:
  preferred_term: Brugada syndrome
  term:
    id: MONDO:0015263
    label: Brugada syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0015263
      label: Brugada syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for this Brugada syndrome root entry.
  - term:
      id: MONDO:0013146
      label: Brugada syndrome 7
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >
      MONDO:0013146 is_a the MONDO:0015263 anchor of this entry and is defined as
      its SCN3B subtype (intersection_of RO:0004003 HGNC:20665). The SCN3B-Brugada
      association rests on heterologous-expression reports of reduced sodium
      current without informative segregation data (PMID:20031595,
      PMID:23257389, PMID:39761910), and was reclassified as disputed by the
      ClinGen Brugada gene-validity reappraisal (PMID:29959160) — and refuted
      outright by ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert
      Panel in December 2025 — on the grounds
      that the two originally implicated variants occur in the general
      population at or above the prevalence of the disease, so it is covered
      here inside the disputed and unresolved non-SCN5A heterogeneity this entry
      curates rather than as a standalone disease root or as a peer subtype of the
      definitive SCN5A form. narrowMatch rather than exactMatch because the anchor
      also subsumes the SCN5A form and the genotype-negative majority stratum that
      this gene-restricted child term excludes.
  - term:
      id: MONDO:0012728
      label: Brugada syndrome 2
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      The GPD1L child term of this entry's anchor. GPD1L was identified by genetic
      linkage rather than by candidate-gene screening, but the ClinGen Brugada
      gene-validity reappraisal (PMID:29959160) still classified it as disputed —
      the linked region was about 24 million base pairs and was not
      comprehensively sequenced, the reported variant is now seen in about 1 in
      5000 individuals in public databases, and no further family has been
      described since the 2002 seminal report. ClinGen's Brugada Syndrome Gene
      Curation Expert Panel records the same disputed classification against
      Brugada syndrome 1. Covered here inside the disputed non-SCN5A
      heterogeneity this entry curates rather than as a subtype row.
  - term:
      id: MONDO:0012742
      label: Brugada syndrome 3
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      The CACNA1C child term. MONDO does not put a `RO:0004003` gene edge on this
      term directly; it inherits CACNA1C through a second parent,
      `MONDO:0700321 CACNA1C-related disorder`, which is why a gene-keyed diff
      over this series does not see it. ClinGen's Hereditary Cardiovascular
      Disease Gene Curation Expert Panel classified CACNA1C for Brugada syndrome
      as disputed in 2025, and the earlier reappraisal found segregation in only
      2 individuals in 2 generations. The gene's definitive disease, Timothy
      syndrome, is curated separately in this KB.
  - term:
      id: MONDO:0012743
      label: Brugada syndrome 4
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      The CACNB2 child term. CACNB2 is one of only three reported Brugada genes
      with more than two segregations within a family, but the reappraisal's
      curators found a reported affected individual in that family who did not
      carry the variant, and ClinGen's current assertion for CACNB2 — made
      against the broader `MONDO:0100547 cardiogenetic disease` rather than
      against Brugada syndrome — is disputed. Covered here rather than as a
      subtype row.
  - term:
      id: MONDO:0013015
      label: Brugada syndrome 5
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      The SCN1B child term. SCN1B is among the 13 genes whose seminal manuscripts
      reported rare variants in sporadic cases only, with no segregation data and
      no evidence of rare-variant excess against controls, and ClinGen's Brugada
      Syndrome Gene Curation Expert Panel classifies it as disputed. Covered here
      rather than as a subtype row.
  - term:
      id: MONDO:0013145
      label: Brugada syndrome 6
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      The KCNE3 child term. KCNE3 is the second of the three genes reported with
      more than two segregations, but the reappraisal judged those four
      segregations insufficient without statistical data, further families or
      other supporting literature, and ClinGen restated the disputed
      classification in 2025. Covered here rather than as a subtype row.
  - term:
      id: MONDO:0013148
      label: Brugada syndrome 8
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      The HCN4 child term. HCN4 is among the 13 genes whose seminal manuscripts
      reported rare variants in sporadic cases only, with no segregation data and
      no evidence of rare-variant excess against controls, and ClinGen's Brugada
      Syndrome Gene Curation Expert Panel classifies it as disputed for Brugada
      syndrome. HCN4 does carry a separate ClinGen assertion for sick sinus
      syndrome 2, which is a different disease and not this entry's concern.
      Covered here rather than as a subtype row.
  - term:
      id: MONDO:0014621
      label: Brugada syndrome 9
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      The KCND3 child term. KCND3 is among the 13 genes whose seminal manuscripts
      reported rare variants in sporadic cases only, with no segregation data and
      no evidence of rare-variant excess against controls, and ClinGen's Brugada
      Syndrome Gene Curation Expert Panel classifies it as disputed. Covered here
      rather than as a subtype row.
parents:
- Cardiac Arrhythmia
- Channelopathy
classifications:
  channelopathy_category:
    classification_value: cardiac channelopathy
    evidence:
    - reference: PMID:33797273
      reference_title: Single-cell transcriptomics trajectory and molecular convergence of clinically relevant mutations in Brugada syndrome.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "Our study suggests that genomic and proteomic hotspots in BrS converge into ion transport pathway and cardiomyocyte as a major BrS-associated cell type that provides insight into the complex genetic etiology of BrS."
      explanation: Supports classification of Brugada syndrome as a cardiomyocyte ion-transport channelopathy.
has_subtypes:
- name: SCN5A-related Brugada syndrome
  subtype_term:
    preferred_term: SCN5A-related Brugada syndrome
    term:
      id: MONDO:0011001
      label: Brugada syndrome 1
  description: >-
    Best-supported monogenic Brugada subtype. Pathogenic SCN5A variants reduce
    NaV1.5-mediated inward sodium current, causing a depolarization-predominant
    Brugada phenotype with characteristic right-precordial ST elevation and
    ventricular arrhythmia risk. This subtype accounts for only a minority of
    clinically diagnosed Brugada syndrome but remains the dominant
    high-confidence gene-disease association.
  genes:
  - preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  evidence:
  - reference: PMID:35004896
    reference_title: "The Mechanism of Ajmaline and Thus Brugada Syndrome: Not Only the Sodium Channel!"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "However, pathogenic rare variants in SCN5A are identified in only 20-30% of cases, and recent data indicates that SCN5A variants are actually, in many cases, prognostic rather than diagnostic, resulting in a more severe phenotype."
    explanation: Supports SCN5A as the major established monogenic subtype while emphasizing that it explains only a minority of clinically diagnosed Brugada syndrome.
  - reference: PMID:33797273
    reference_title: Single-cell transcriptomics trajectory and molecular convergence of clinically relevant mutations in Brugada syndrome.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "We observed an over-representation of clinically relevant mutations (∼80%) in SCN5A gene and also identified several candidate genes, including GPD1L, TRPM4, and SCN10A."
    explanation: Shows that SCN5A dominates the curated high-confidence variant landscape within Brugada syndrome while other genes remain secondary candidates.
- name: Oligogenic Brugada syndrome
  display_name: Genotype-negative or oligogenic Brugada syndrome
  description: >-
    Majority stratum of clinically diagnosed Brugada syndrome in which no
    single definitive monogenic cause is identified. Current evidence supports a
    heterogeneous architecture involving unresolved rare variation, common
    variant burden, and multiple non-SCN5A candidate genes that should not be
    promoted to standalone disease roots without stronger evidence. Despite the
    subtype name, no oligogenic inheritance term (HP:0010983) is bound and this
    entry is not a member of the Digenic and Oligogenic Disorders grouping. The
    cited evidence establishes that 70-85% of cases are genetically unresolved,
    which is an absence of a monogenic explanation rather than a demonstration
    of two or a few co-transmitted loci; a common-variant burden architecture
    would in any case be polygenic (HP:0010982), not oligogenic. The subtype is
    retained under its published name because that is how the stratum is
    labelled in the literature.
  evidence:
  - reference: PMID:32121523
    reference_title: "Brugada Syndrome: Oligogenic or Mendelian Disease?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Although BrS is considered a genetic disease, its molecular mechanism remains elusive in about 70-85% of clinically-confirmed cases."
    explanation: Establishes that most clinically confirmed Brugada syndrome remains genetically unresolved.
  - reference: PMID:32121523
    reference_title: "Brugada Syndrome: Oligogenic or Mendelian Disease?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Variants occurring in at least 26 different genes have been previously considered causative, although the causative effect of all but the SCN5A gene has been recently challenged, due to the lack of systematic, evidence-based evaluations, such as a variant's frequency among the general population, family segregation analyses, and functional studies."
    explanation: Supports treating non-SCN5A Brugada genes as unresolved or disputed heterogeneity rather than as established monogenic roots.
  - reference: PMID:20301690
    reference_title: Brugada Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      A molecular diagnosis can be established in an individual with
      characteristic features and identification of a heterozygous pathogenic
      variant in SCN5A or one of the additional 42 genes associated with Brugada
      syndrome.
    explanation: >-
      The GeneReviews chapter still lists 42 non-SCN5A genes as diagnostic, which
      the ClinGen reappraisal cited on this entry's SCN3B record contradicts for
      20 of the 21 it curated. Recorded here because the disagreement is between
      two standard sources rather than between a source and this entry, and it is
      what this subtype exists to hold.
definitions:
- name: >-
    Fever-associated type-1 Brugada ECG case-finding query for latent
    SCN5A/Brugada carriers
  definition_type: PHENOTYPE_ALGORITHM
  derivation_basis: ESTABLISHED_CRITERIA
  validation_status:
    status: UNVALIDATED
    rationale: >-
      Fever-unmasking of the type-1 Brugada ECG is an established, clinically
      recognized phenomenon (guidelines advise recording an ECG during fever),
      so the query is well grounded — but this specific computable EHR phenotype
      has not been evaluated against a genotyped gold standard for PPV/yield.
      Validation substrate: a genotype-linked EHR biobank (eMERGE, All of Us, UK
      Biobank); MIMIC-IV-ECG can prototype the type-1 morphology detector but
      lacks the linked DNA needed to confirm SCN5A carriership.
  attaches_to:
  - pathophysiology#Fever-induced accentuation of sodium-channel loss of function
  description: >-
    EHR/OMOP case-finding query: identify individuals in whom a type-1 coved
    Brugada ECG (or a fever-triggered ventricular arrhythmia) is documented
    during a febrile episode, as candidates for latent/undiagnosed Brugada
    syndrome warranting off-fever confirmation and SCN5A evaluation. Contrast
    with the Timothy fever query: here the fever→unmasking mechanism is
    established, so derivation_basis is ESTABLISHED_CRITERIA rather than
    MECHANISTIC_HYPOTHESIS.
  scope: >-
    EHR/OMOP case-finding for latent Brugada carriers; grounded in established
    fever-unmasking biology but not yet validated as a computable phenotype.
  criteria_sets:
  - name: Fever-associated type-1 Brugada ECG
    description: >-
      A type-1 coved right-precordial ST-segment elevation, or a ventricular
      tachyarrhythmia, documented during a febrile episode in a patient without a
      prior Brugada diagnosis; confirm off-fever and refer for SCN5A testing.
    inclusion_criteria:
    - preferred_term: Documented febrile episode
      description: Elevated body temperature or a febrile-illness diagnosis code (index exposure).
    - preferred_term: Type-1 Brugada ECG or fever-triggered ventricular arrhythmia
      description: >-
        Coved type-1 right-precordial ST-segment elevation, or a ventricular
        tachyarrhythmia, recorded during the febrile episode.
    exclusion_criteria:
    - preferred_term: Pre-existing Brugada diagnosis
      description: Already-diagnosed Brugada syndrome (not a latent-case-finding hit).
  evidence:
  - reference: PMID:27033637
    reference_title: Prognostic significance of fever-induced Brugada syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One hundred twelve patients with BrS who developed F-type1 were
      retrospectively enrolled.
    explanation: >-
      Establishes fever-induced type-1 Brugada ECG as an identifiable clinical
      cohort — the population this query targets.
  - reference: PMID:27033637
    reference_title: Prognostic significance of fever-induced Brugada syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "26.4% (14 of 53) carried a pathogenic SCN5A mutation."
    explanation: >-
      A substantial fraction of fever-induced type-1 patients carry a pathogenic
      SCN5A variant, supporting the case-finding rationale that fever-provoked
      type-1 ECG enriches for genotype-positive carriers.
  notes: >-
    Worked ESTABLISHED-basis counterpart to the Timothy fever_exacerbated_cav1.2
    query: same trigger-provoked-latent-disease archetype, but the fever→Nav1.5
    unmasking mechanism is settled, so derivation_basis is ESTABLISHED_CRITERIA
    (validation_status UNVALIDATED for the computable phenotype itself). See
    docs/hypothesis-based-phenotype-algorithms.md and
    docs/reports/hypothesis-driven-ehr-case-finding-2026-07-12.md.
pathophysiology:
- name: Reduced Depolarization Reserve
  conforms_to: "cardiac_ion_channel_repolarization#Cardiac Ion-Channel or Calcium-Handling Variant"
  role: trigger
  description: >-
    Brugada syndrome converges on reduced depolarizing reserve in ventricular
    cardiomyocytes, most often through decreased inward sodium current but also
    through broader ion-current imbalance involving calcium and potassium
    channel pathways. At the disease level, the key mechanistic theme is not
    long-QT-like delayed repolarization alone but reduced inward current and
    impaired conduction reserve in the right ventricular substrate.
  genes:
  - preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
    modifier: LOSS_OF_FUNCTION
  - preferred_term: SCN3B
    term:
      id: hgnc:20665
      label: SCN3B
    modifier: LOSS_OF_FUNCTION
  notes: >-
    The two genes on this node are not graded alike, and the difference is in
    `genetic:` rather than here. SCN5A is CAUSATIVE. SCN3B is DISPUTED: the
    ClinGen Brugada reappraisal rejected its reported alleles on population
    frequency and absent segregation, while the mechanism those alleles were
    reported to act through — reduced peak sodium current in ventricular
    myocytes — is the mechanism this node represents and is supported in the
    Scn3b-null mouse. SCN3B is bound here because the mechanism claim is the one
    a pathograph node makes; read the allele-level verdict off its `genetic:`
    record. Note that the KGX exporter reads neither `relationship_type` nor this
    note (dismech#12320), so a downstream consumer of the export will see the two
    genes undifferentiated.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: right ventricular cardiomyocyte
    term:
      id: CL:2000046
      label: ventricular cardiac muscle cell
  molecular_functions:
  - preferred_term: monoatomic ion channel activity
    term:
      id: GO:0005216
      label: monoatomic ion channel activity
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: membrane depolarization during cardiac muscle cell action potential
    term:
      id: GO:0086012
      label: membrane depolarization during cardiac muscle cell action potential
    modifier: DECREASED
  - preferred_term: cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: DECREASED
  - preferred_term: sodium ion transport
    term:
      id: GO:0006814
      label: sodium ion transport
    modifier: DECREASED
  locations:
  - preferred_term: outflow tract of right ventricle
    term:
      id: UBERON:0005953
      label: outflow part of right ventricle
  evidence:
  - reference: PMID:33797273
    reference_title: Single-cell transcriptomics trajectory and molecular convergence of clinically relevant mutations in Brugada syndrome.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Our study suggests that genomic and proteomic hotspots in BrS converge into ion transport pathway and cardiomyocyte as a major BrS-associated cell type that provides insight into the complex genetic etiology of BrS."
    explanation: Supports ion-transport dysregulation in cardiomyocytes as the convergent disease-level mechanism across genetically heterogeneous Brugada syndrome.
  - reference: PMID:29024690
    reference_title: Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patient.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient-derived iPS-CM showed a 33.1-45.5% reduction in INa density, a shift in both activation and inactivation voltage-dependence curves, and faster recovery from inactivation."
    explanation: Directly demonstrates reduced inward sodium current and altered channel gating in a patient-specific SCN5A Brugada cardiomyocyte model.
  downstream:
  - target: Type 1 coved ST-segment elevation
    description: Reduced depolarization reserve in the right-precordial substrate produces the diagnostic coved ST-segment elevation pattern.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27803673
      reference_title: "Electrophysiological Mechanisms of Brugada Syndrome: Insights from Pre-clinical and Clinical Studies."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "Computational modeling work demonstrated that the balance between inward and outward currents could affect excitation and the ST segment elevation in concert"
      explanation: Supports altered inward-versus-outward current balance as a cause of excitation failure and Brugada ST elevation.
  - target: RVOT Conduction Slowing
    description: Reduced depolarizing reserve lowers excitation wavelength and promotes localized conduction delay in the right ventricular outflow tract substrate.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27803673
      reference_title: "Electrophysiological Mechanisms of Brugada Syndrome: Insights from Pre-clinical and Clinical Studies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The depolarization theory proposes that slower upstroke of phase 0 and the consequent reduction in conduction velocity (CV) of the APs are responsible for arrhythmogenesis."
      explanation: Supports reduced phase-0 depolarization as the cause of slowed conduction in the Brugada substrate.
- name: RVOT Conduction Slowing
  conforms_to: "cardiac_ion_channel_repolarization#Arrhythmogenic Substrate and Triggered Activity"
  role: amplifier
  description: >-
    Tissue-level Brugada pathophysiology includes delayed depolarization and
    conduction dispersion in the right ventricular outflow tract, where reduced
    conduction reserve creates the proximate substrate for malignant ventricular
    arrhythmia. Heterogeneous, slowed depolarization and conduction across the
    RVOT constitute the depolarization-predominant arrhythmogenic substrate of
    Brugada syndrome.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: right ventricular cardiomyocyte
    term:
      id: CL:2000046
      label: ventricular cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac muscle cell action potential
    term:
      id: GO:0086001
      label: cardiac muscle cell action potential
    modifier: ABNORMAL
  - preferred_term: cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: DYSREGULATED
  locations:
  - preferred_term: outflow tract of right ventricle
    term:
      id: UBERON:0005953
      label: outflow part of right ventricle
  evidence:
  - reference: PMID:27803673
    reference_title: "Electrophysiological Mechanisms of Brugada Syndrome: Insights from Pre-clinical and Clinical Studies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These are in keeping with clinical findings of delayed depolarization in the RV outflow tract demonstrated using electroanatomical mapping"
    explanation: Supports delayed depolarization and conduction slowing in the RV outflow tract as an atomic tissue-level Brugada mechanism.
  - reference: PMID:27803673
    reference_title: "Electrophysiological Mechanisms of Brugada Syndrome: Insights from Pre-clinical and Clinical Studies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Decreased λ has been associated with increased likelihood of reentrant arrhythmias"
    explanation: Supports reduced excitation wavelength from slowed conduction as the tissue-level substrate that raises reentrant ventricular arrhythmia likelihood in Brugada syndrome.
  downstream:
  - target: Current-Load Mismatch at RVOT Substrate
    description: Structural discontinuities in the RVOT coexist with conduction delay and convert reduced conduction reserve into excitation failure and conduction block.
    evidence:
    - reference: PMID:27803673
      reference_title: "Electrophysiological Mechanisms of Brugada Syndrome: Insights from Pre-clinical and Clinical Studies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "It was suggested that current-to-load mismatches at discontinuities can cause conduction block."
      explanation: Supports discontinuity-associated current-to-load mismatch as the mechanism converting limited conduction reserve into block.
- name: Current-Load Mismatch at RVOT Substrate
  conforms_to: "cardiac_ion_channel_repolarization#Arrhythmogenic Substrate and Triggered Activity"
  role: amplifier
  description: >-
    Structural abnormalities in the RV and RVOT increase current-to-load
    mismatch and excitation failure, providing a distinct tissue-level
    mechanism that can cooperate with conduction slowing to destabilize the
    Brugada substrate.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: right ventricular cardiomyocyte
    term:
      id: CL:2000046
      label: ventricular cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac muscle cell action potential
    term:
      id: GO:0086001
      label: cardiac muscle cell action potential
    modifier: ABNORMAL
  - preferred_term: cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: DYSREGULATED
  locations:
  - preferred_term: outflow tract of right ventricle
    term:
      id: UBERON:0005953
      label: outflow part of right ventricle
  evidence:
  - reference: PMID:27803673
    reference_title: "Electrophysiological Mechanisms of Brugada Syndrome: Insights from Pre-clinical and Clinical Studies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In patients with Brugada syndrome, structural abnormalities are indeed observed in the RV and RVOT, which would increase current-load mismatch and excitation failure"
    explanation: Supports current-to-load mismatch and local excitation failure as a distinct RV/RVOT substrate mechanism in Brugada syndrome.
  - reference: PMID:27803673
    reference_title: "Electrophysiological Mechanisms of Brugada Syndrome: Insights from Pre-clinical and Clinical Studies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It was suggested that current-to-load mismatches at discontinuities can cause conduction block."
    explanation: Supports current-to-load mismatch at structural discontinuities as a mechanistic source of conduction block in the Brugada substrate.
  downstream:
  - target: Malignant Ventricular Tachyarrhythmia
    description: Excitation failure and conduction block in the RVOT substrate promote reentrant polymorphic VT and VF.
    evidence:
    - reference: PMID:27803673
      reference_title: "Electrophysiological Mechanisms of Brugada Syndrome: Insights from Pre-clinical and Clinical Studies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "It should be recognized that abnormal depolarization does not act in isolation, but act in concert with discontinuous conduction to produce arrhythmias in BrS"
      explanation: Supports excitation failure and discontinuous conduction as cooperating causes of Brugada arrhythmias.
- name: Malignant Ventricular Tachyarrhythmia
  conforms_to: "cardiac_ion_channel_repolarization#Ventricular Tachyarrhythmia"
  role: effector
  description: >-
    The clinical consequence of the Brugada substrate is malignant ventricular
    tachyarrhythmia, especially polymorphic ventricular tachycardia and
    ventricular fibrillation, with syncope or sudden cardiac death as the major
    downstream manifestations.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:39896197
    reference_title: Brugada syndrome update.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This condition, identified by Josep and Pedro Brugada, is often marked by symptoms such as syncope and episodes of polymorphic ventricular tachycardia (PVT) or ventricular fibrillation (VF)."
    explanation: Defines the characteristic malignant ventricular arrhythmias and their clinical presentation in Brugada syndrome.
  - reference: PMID:39896197
    reference_title: Brugada syndrome update.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These arrhythmias, if not managed promptly, can escalate to sudden cardiac death (SCD), notably in patients whose cardiac structure appears normal."
    explanation: Links Brugada-associated ventricular tachyarrhythmia directly to sudden cardiac death risk.
  downstream:
  - target: Polymorphic ventricular tachycardia
    description: The Brugada arrhythmogenic substrate can produce polymorphic ventricular tachycardia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39896197
      reference_title: Brugada syndrome update.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "This condition, identified by Josep and Pedro Brugada, is often marked by symptoms such as syncope and episodes of polymorphic ventricular tachycardia (PVT) or ventricular fibrillation (VF)."
      explanation: Supports polymorphic ventricular tachycardia as a direct manifestation of the Brugada arrhythmogenic substrate.
  - target: Ventricular fibrillation
    description: The Brugada arrhythmogenic substrate can degenerate into ventricular fibrillation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39896197
      reference_title: Brugada syndrome update.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "This condition, identified by Josep and Pedro Brugada, is often marked by symptoms such as syncope and episodes of polymorphic ventricular tachycardia (PVT) or ventricular fibrillation (VF)."
      explanation: Supports ventricular fibrillation as a direct manifestation of the Brugada arrhythmogenic substrate.
  - target: Syncope and Sudden Cardiac Death
    description: Sustained polymorphic ventricular tachycardia or ventricular fibrillation abolishes effective cardiac output, producing syncope and, if not terminated, sudden cardiac death.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39896197
      reference_title: Brugada syndrome update.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "These arrhythmias, if not managed promptly, can escalate to sudden cardiac death (SCD), notably in patients whose cardiac structure appears normal."
      explanation: Supports malignant ventricular arrhythmia as the proximate cause of sudden cardiac death in Brugada syndrome.
- name: Syncope and Sudden Cardiac Death
  conforms_to: "cardiac_ion_channel_repolarization#Syncope and Sudden Cardiac Death"
  role: outcome
  description: >-
    Loss of effective cardiac output from sustained Brugada-associated
    polymorphic ventricular tachycardia or ventricular fibrillation causes
    transient cerebral hypoperfusion (syncope) and, when the arrhythmia does not
    self-terminate, sudden cardiac death. These are the shared clinical
    endpoints of Brugada syndrome and are frequently the sentinel manifestation
    in structurally normal hearts.
  evidence:
  - reference: PMID:39896197
    reference_title: Brugada syndrome update.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These arrhythmias, if not managed promptly, can escalate to sudden cardiac death (SCD), notably in patients whose cardiac structure appears normal."
    explanation: Supports syncope/sudden cardiac death as the terminal outcome of Brugada-associated ventricular tachyarrhythmia in structurally normal hearts.
  - reference: PMID:23499630
    reference_title: "Prevalence, characteristics, and prognosis role of type 1 ST elevation in the peripheral ECG leads in patients with Brugada syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "72 (22%) patients presented with unexplained syncope, and 26 (8%) patients presented with sudden death (12 patients) or appropriated implantable cardioverter-defibrillator therapies (14 patients)"
    explanation: Human cohort evidence documenting unexplained syncope and sudden death (or appropriate ICD therapy) as the clinical outcomes in Brugada syndrome patients.
  downstream:
  - target: Syncope
    description: >-
      Syncope is a clinical outcome in Brugada syndrome; the cited cohort
      classified these events as unexplained and therefore does not establish a
      documented ventricular tachyarrhythmia for each episode.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23499630
      reference_title: "Prevalence, characteristics, and prognosis role of type 1 ST elevation in the peripheral ECG leads in patients with Brugada syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "72 (22%) patients presented with unexplained syncope, and 26 (8%) patients presented with sudden death (12 patients) or appropriated implantable cardioverter-defibrillator therapies (14 patients)"
      explanation: >-
        The cohort supports syncope as an observed clinical outcome but does not
        attribute each unexplained episode to a recorded arrhythmia.
  - target: Sudden cardiac death
    description: Sustained ventricular tachyarrhythmia that does not terminate causes sudden cardiac death.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39896197
      reference_title: Brugada syndrome update.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "These arrhythmias, if not managed promptly, can escalate to sudden cardiac death (SCD), notably in patients whose cardiac structure appears normal."
      explanation: Supports unterminated ventricular arrhythmia as the cause of sudden cardiac death.
- name: Fever-induced accentuation of sodium-channel loss of function
  role: trigger
  description: >-
    Elevated body temperature accentuates the loss of function of the cardiac
    sodium channel (Nav1.5/SCN5A) that underlies Brugada syndrome. The
    Brugada-associated SCN5A mutation Thr1620Met is arrhythmogenic only at
    temperatures approaching the physiological range, so fever transiently
    worsens the depolarization-reserve deficit — unmasking or accentuating the
    diagnostic type-1 coved ST-segment elevation and, in some patients,
    precipitating malignant ventricular arrhythmia. Unlike the Timothy-syndrome
    fever effect (an emerging, model-system hypothesis), fever-unmasking of the
    Brugada ECG is an established clinical phenomenon.
  gene:
    preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  cell_types:
  - preferred_term: right ventricular cardiomyocyte
    term:
      id: CL:2000046
      label: ventricular cardiac muscle cell
  molecular_functions:
  - preferred_term: voltage-gated sodium channel activity
    term:
      id: GO:0005248
      label: voltage-gated sodium channel activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: cellular response to heat
    term:
      id: GO:0034605
      label: cellular response to heat
    modifier: INCREASED
  locations:
  - preferred_term: outflow tract of right ventricle
    term:
      id: UBERON:0005953
      label: outflow part of right ventricle
  evidence:
  - reference: PMID:10532948
    reference_title: >-
      Ionic mechanisms responsible for the electrocardiographic phenotype of the
      Brugada syndrome are temperature dependent.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      illustrate for the first time a cardiac sodium channel mutation of which
      the arrhythmogenicity is revealed only at temperatures approaching the
      physiological range, and suggest that some patients may be more at risk
      during febrile states
    explanation: >-
      Patch-clamp study of the SCN5A Thr1620Met Brugada mutation shows its
      arrhythmogenic gating defect emerges near physiological temperature,
      establishing the temperature-dependence that makes fever an unmasking
      trigger.
  - reference: PMID:32015236
    reference_title: >-
      Electrocardiogram Characteristics and Arrhythmic Events during Fever in
      Patients with Fever-Induced Brugada Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fever may not only reveal BrS but also induce life-threatening arrhythmic
      events, especially in children and adolescents
    explanation: >-
      Clinical series confirming that fever both unmasks the Brugada pattern and
      can precipitate malignant arrhythmia.
  downstream:
  - target: Type 1 coved ST-segment elevation
    description: >-
      Fever accentuates sodium-channel loss of function and unmasks or augments
      the diagnostic type-1 coved ST-segment elevation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32015236
      reference_title: >-
        Electrocardiogram Characteristics and Arrhythmic Events during Fever in
        Patients with Fever-Induced Brugada Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the J point increased significantly in precordial leads V1, V2, and V3
        during the febrile state
      explanation: >-
        Quantifies fever-induced accentuation of right-precordial ST/J-point
        elevation, the diagnostic Brugada pattern.
  - target: Malignant Ventricular Tachyarrhythmia
    description: >-
      In some patients fever precipitates fever-triggered malignant ventricular
      arrhythmia on the accentuated Brugada substrate.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - accentuated RVOT conduction slowing
    evidence:
    - reference: PMID:32015236
      reference_title: >-
        Electrocardiogram Characteristics and Arrhythmic Events during Fever in
        Patients with Fever-Induced Brugada Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Fever may not only reveal BrS but also induce life-threatening arrhythmic events, especially in children and adolescents"
      explanation: Clinical evidence supports fever as a trigger of malignant arrhythmic events in Brugada syndrome.
phenotypes:
- category: Cardiovascular
  name: Type 1 coved ST-segment elevation
  diagnostic: true
  description: >-
    Diagnostic right-precordial type 1 Brugada ECG pattern with coved ST-segment
    elevation, spontaneous or sodium-channel-blocker-provoked.
  phenotype_term:
    preferred_term: Type 1 coved ST-segment elevation
    term:
      id: HP:6000984
      label: Coved type ST segment elevation
  evidence:
  - reference: PMID:20233789
    reference_title: "Number of electrocardiogram leads displaying the diagnostic coved-type pattern in Brugada syndrome: a diagnostic consensus criterion to be revised."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "According to the diagnostic consensus criteria, the electrocardiographic (ECG) diagnosis of Brugada syndrome requires coved-type > or =2 mm ST-segment elevation in >1 right precordial lead (RPL) V1-V3 in the presence or absence of a sodium-channel blocker."
    explanation: Supports the hallmark diagnostic ECG phenotype for Brugada syndrome.
- category: Cardiovascular
  name: Syncope
  description: >-
    Unexplained syncope due to transient ventricular tachyarrhythmia is a common
    symptomatic presentation in clinically recognized Brugada syndrome.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
  evidence:
  - reference: PMID:23499630
    reference_title: "Prevalence, characteristics, and prognosis role of type 1 ST elevation in the peripheral ECG leads in patients with Brugada syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two hundred twenty-five (70%) patients were asymptomatic, 72 (22%) patients presented with unexplained syncope, and 26 (8%) patients presented with sudden death (12 patients) or appropriated implantable cardioverter-defibrillator therapies (14 patients) at diagnosis or over a mean follow-up of 48 ± 34 months."
    explanation: Provides cohort-level evidence that syncope is a common presenting manifestation in Brugada syndrome.
- category: Cardiovascular
  name: Polymorphic ventricular tachycardia
  description: >-
    Symptomatic or abortive malignant ventricular tachyarrhythmia arising from
    the Brugada substrate.
  phenotype_term:
    preferred_term: polymorphic ventricular tachycardia
    term:
      id: HP:0031677
      label: Polymorphic ventricular tachycardia
  evidence:
  - reference: PMID:39896197
    reference_title: Brugada syndrome update.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This condition, identified by Josep and Pedro Brugada, is often marked by symptoms such as syncope and episodes of polymorphic ventricular tachycardia (PVT) or ventricular fibrillation (VF)."
    explanation: Supports polymorphic ventricular tachycardia as a canonical malignant arrhythmia in Brugada syndrome.
- category: Cardiovascular
  name: Ventricular fibrillation
  description: >-
    Ventricular fibrillation is a defining malignant arrhythmia in Brugada
    syndrome and a proximate cause of cardiac arrest.
  phenotype_term:
    preferred_term: Ventricular fibrillation
    term:
      id: HP:0001663
      label: Ventricular fibrillation
  evidence:
  - reference: PMID:39896197
    reference_title: Brugada syndrome update.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This condition, identified by Josep and Pedro Brugada, is often marked by symptoms such as syncope and episodes of polymorphic ventricular tachycardia (PVT) or ventricular fibrillation (VF)."
    explanation: Supports ventricular fibrillation as a core malignant arrhythmia phenotype in Brugada syndrome.
- category: Cardiovascular
  name: Sudden cardiac death
  description: >-
    Sudden cardiac death occurs when Brugada-associated polymorphic VT or VF is
    not promptly terminated.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:39896197
    reference_title: Brugada syndrome update.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These arrhythmias, if not managed promptly, can escalate to sudden cardiac death (SCD), notably in patients whose cardiac structure appears normal."
    explanation: Supports sudden cardiac death as the principal life-threatening outcome of Brugada-associated ventricular arrhythmia.
genetic:
- name: SCN5A loss-of-function variants
  association: Causative
  relationship_type: CAUSATIVE
  subtype: SCN5A-related Brugada syndrome
  features: >-
    SCN5A is the strongest monogenic Brugada gene and defines the classic
    NaV1.5 loss-of-function subtype. SCN5A accounts for a minority of all
    clinically diagnosed Brugada syndrome but dominates the curated
    high-confidence variant literature and often marks a more severe phenotype.
    It is the only one of the 21 genes the ClinGen Brugada reappraisal curated
    that reached a definitive classification, and ClinGen's current assertion is
    definitive — made not against Brugada syndrome itself but against
    MONDO:1010181 SCN5A-related cardiac rhythm disorder, the gene-named concept
    that MONDO also uses as the second parent of Brugada syndrome 1. That routing
    is why MONDO carries no direct causal-gene edge on MONDO:0011001: the gene is
    inherited from the gene-named parent, so a gene-keyed comparison over the
    numbered Brugada series does not see the SCN5A form at all.
  gene_term:
    preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  evidence:
  - reference: PMID:35004896
    reference_title: "The Mechanism of Ajmaline and Thus Brugada Syndrome: Not Only the Sodium Channel!"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "However, pathogenic rare variants in SCN5A are identified in only 20-30% of cases, and recent data indicates that SCN5A variants are actually, in many cases, prognostic rather than diagnostic, resulting in a more severe phenotype."
    explanation: Shows that SCN5A is clinically important but explains only a minority of diagnosed Brugada syndrome, consistent with a root entry plus subtype model.
  - reference: PMID:33797273
    reference_title: Single-cell transcriptomics trajectory and molecular convergence of clinically relevant mutations in Brugada syndrome.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "We observed an over-representation of clinically relevant mutations (∼80%) in SCN5A gene and also identified several candidate genes, including GPD1L, TRPM4, and SCN10A."
    explanation: Supports SCN5A as the dominant high-confidence gene within the clinically curated Brugada variant landscape.
  - reference: CGGV:assertion_9f832392-a92b-408d-8d1a-e2037905fab3-2025-10-08T160000.000Z
    reference_title: "SCN5A / SCN5A-related cardiac rhythm disorder (Definitive)"
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    snippet: "SCN5A | HGNC:10593 | SCN5A-related cardiac rhythm disorder | MONDO:1010181 | AD | Definitive | SOP11 | Hereditary Cardiovascular Disease Gene Curation Expert Panel | 2025-10-08T16:00:00.000Z"
    explanation: >-
      ClinGen's current definitive assertion for SCN5A, and the source for this
      record's statement that it is made against the gene-named concept
      MONDO:1010181 rather than against Brugada syndrome.
  - reference: PMID:29959160
    reference_title: "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    snippet: "The SCN5A gene was the only gene, among the 21 curated, to be classified as definitive by all 3 curation teams."
    explanation: >-
      Establishes SCN5A as the single gene in the reappraisal that all three
      curation teams classified as definitive, which is what separates this record
      from the eight disputed ones below it.
- name: SCN3B variants
  association: Disputed
  relationship_type: DISPUTED
  features: >-
    SCN3B encodes the auxiliary beta-3 subunit of the cardiac voltage-gated
    sodium channel and is the gene behind the numbered series term Brugada
    syndrome 7 (MONDO:0013146). The association rests principally on two
    variants: L10P, reported in a single American proband, and V110I, found in
    3 of 178 SCN5A-negative Japanese patients. Both were reported to impair
    cytoplasmic trafficking of Nav1.5 and reduce sodium current in transfected
    cells, converging on the same depolarization-reserve node this entry already
    curates for SCN5A. A third variant, T138del, was reported in 2025 with
    preserved beta-3 surface expression and preserved Nav1.5 interaction but
    reduced peak current, so reduced sodium current rather than mistrafficking
    is the common thread. The gene-disease claim nonetheless failed reappraisal:
    no report provided informative segregation data, and both of the originally
    implicated variants were subsequently found at a heterozygosity frequency of
    about 1 in 2500 in public population databases, which the ClinGen Brugada
    gene-validity reappraisal judged to be at or above the population prevalence
    of Brugada syndrome and therefore incompatible with a highly penetrant
    monogenic causal role. That reappraisal reclassified SCN3B, with 19 other
    curated Brugada genes, as disputed. Two further observations point the same
    way: L10P, the original Brugada allele, was independently reported in a lone
    atrial fibrillation cohort. The in vivo evidence, by contrast, cuts toward
    the mechanism rather than against it: the Scn3b-null mouse has reduced peak
    sodium current in ventricular myocytes and inducible ventricular
    tachycardia, which its authors describe as resembling Scn5a heterozygous
    hearts, alongside sinoatrial and atrioventricular conduction disease. What
    that model cannot settle is the human allele question, since it is a
    homozygous null while the reported patient variants are heterozygous. SCN3B
    is therefore curated as part of the disputed non-SCN5A heterogeneity rather
    than as a validated monogenic cause: the mechanism is plausible and
    supported in vivo, and the specific reported alleles are what fail. ClinGen
    has since gone further than the 2018 reappraisal: its Hereditary
    Cardiovascular Disease Gene Curation Expert Panel classified SCN3B for
    Brugada syndrome as refuted in December 2025, not merely disputed. This
    record keeps `relationship_type: DISPUTED` because that enum has no refuted
    value, and the refutation is stated here and carried by the ClinGen evidence
    item below.
  gene_term:
    preferred_term: SCN3B
    term:
      id: hgnc:20665
      label: SCN3B
  evidence:
  - reference: PMID:20031595
    reference_title: A mutation in the beta 3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "Coexpression of SCN5A/WT+SCN1B/WT+SCN3B/L10P resulted in an 82.6% decrease in peak sodium current density, accelerated inactivation, slowed reactivation, and a -9.6-mV shift of half-inactivation voltage compared with SCN5A/WT+SCN1B/WT+SCN3B/WT."
    explanation: >-
      The heterologous-expression result that is the entire functional basis for
      the SCN3B-Brugada association, and the reason the reported mechanism is a
      reduction in sodium current.
  - reference: PMID:20031595
    reference_title: A mutation in the beta 3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "A missense mutation (L10P) was detected in exon 1 of SCN3B, the beta 3 subunit of the cardiac sodium channel, but not in any other gene known to be associated with Brugada syndrome or in 296 controls."
    explanation: >-
      Establishes the human observation behind the association: a single proband
      carrying L10P, absent from 296 controls.
  - reference: PMID:29959160
    reference_title: "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome."
    supports: REFUTE
    directness: DIRECT
    evidence_source: OTHER
    snippet: "Seminal manuscripts for 13 of the 19 genes reported rare variants in only sporadic cases with no segregation data or evidence of rare variant excess compared with control subjects (ABCC9, ANK2, CACNA2D1, HCN4, KCND3, KCNH2, KCNJ8, RANGRF, SCN1B, SCN2B, SCN3B, SLMAP, TRPM4)."
    explanation: >-
      Names SCN3B directly among the genes whose founding reports lacked
      segregation data or rare-variant excess, which is the specific basis for
      the disputed classification here.
  - reference: PMID:23257389
    reference_title: Novel SCN3B mutation associated with brugada syndrome affects intracellular trafficking and function of Nav1.5.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "A mutation, Val110Ile, was identified in 3 of 178 (1.7%) Japanese patients, but was not found in 480 Japanese controls."
    explanation: >-
      The second and larger SCN3B report, giving a cohort frequency in
      SCN5A-negative Brugada syndrome rather than a single proband. Note the
      control screen here is 480 samples; the population-database frequency that
      later undercut this variant is recorded in the REFUTE item below.
  - reference: PMID:23257389
    reference_title: Novel SCN3B mutation associated with brugada syndrome affects intracellular trafficking and function of Nav1.5.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "The SCN3B mutation impaired the cytoplasmic trafficking of Nav1.5, the cell surface expression of which was decreased in transfected cells."
    explanation: >-
      Independently replicates the trafficking-defect mechanism first reported
      for L10P, in a different variant and a different laboratory.
  - reference: PMID:29959160
    reference_title: "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome."
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Two curated genes in this study were originally implicated on the basis of variants suggested to be rare in the original studies, only to be subsequently noted to have heterozygosity frequency in public databases greater than or equal to the prevalence of BrS (KCNJ8 p.Ser422Leu, 1/250; SCN3B p.Leu10Pro, p.Val110Ile, both 1/2500)."
    explanation: >-
      Names both SCN3B variants and gives the specific reason the association
      failed: a population frequency exceeding the prevalence of the disease
      they were said to cause.
  - reference: PMID:39761910
    reference_title: "A novel SCN3B in-frame codon deletion in a Brugada syndrome patient: Implications for disrupted Na(V)1.5 function."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "Biotinylation, co-immunoprecipitation and surface cross-linking experiments identified normal β3 surface expression and interaction with NaV1.5. Electrophysiological analysis identified reduced peak current and channel availability."
    explanation: >-
      A third reported variant whose loss of function does not act through
      mistrafficking, which is why the shared mechanism across SCN3B variants is
      stated here as reduced sodium current rather than impaired trafficking.
  - reference: PMID:21051419
    reference_title: Mutations in sodium channel β-subunit SCN3B are associated with early-onset lone atrial fibrillation.
    supports: REFUTE
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three non-synonymous mutations were found in SCN3B (R6K, L10P, and M161T)."
    explanation: >-
      L10P, the allele on which the original Brugada report rests, was
      independently found in a lone atrial fibrillation cohort. One allele
      reported for two different arrhythmia phenotypes weakens the specific
      claim that it causes Brugada syndrome, though it does not bear on whether
      SCN3B affects sodium current at all, hence INDIRECT.
  - reference: PMID:19796257
    reference_title: Scn3b knockout mice exhibit abnormal sino-atrial and cardiac conduction properties.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Lead I electrocardiograms from Scn3b(-/-) mice showed slower heart rates, longer P wave durations and prolonged PR intervals than WT hearts."
    explanation: >-
      Establishes in vivo that loss of the beta-3 subunit slows cardiac
      conduction, the organism-level counterpart of the reduced sodium current
      measured in transfected cells. Graded INDIRECT because a mouse conduction
      phenotype supports the sodium-channel mechanism by inference rather than
      demonstrating the human Brugada phenotype.
  - reference: PMID:19351516
    reference_title: Scn3b knockout mice exhibit abnormal ventricular electrophysiological properties.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Together, these findings associate the lack of the Scn3b gene with arrhythmic tendencies in intact perfused hearts and electrophysiological features similar to those in Scn5a(+/-) hearts."
    explanation: >-
      The strongest in vivo support for the mechanism: losing beta-3 produces a
      ventricular electrophysiological phenotype the authors read as resembling
      Scn5a heterozygous hearts, the canonical sodium-channel arrhythmia model.
      INDIRECT because it is a homozygous null in mouse rather than the
      heterozygous human alleles whose population frequency is what the disputed
      classification actually rests on.
  - reference: PMID:29959160
    reference_title: "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome."
    supports: REFUTE
    directness: DIRECT
    evidence_source: OTHER
    snippet: "All other genes (20 of 21) received a final classification of disputed with regard to assertions toward causality for BrS by a clinical domain expert panel."
    explanation: >-
      The expert-panel verdict that places SCN3B, along with every other reported
      non-SCN5A Brugada gene, in the disputed tier.
  - reference: CGGV:assertion_a08c3aaa-cae9-4060-b1df-1f24c781bb14-2025-12-16T010000.000Z
    reference_title: "SCN3B / Brugada syndrome (Refuted)"
    supports: REFUTE
    directness: DIRECT
    evidence_source: OTHER
    snippet: "SCN3B | HGNC:20665 | Brugada syndrome | MONDO:0015263 | AD | Refuted | SOP11 | Hereditary Cardiovascular Disease Gene Curation Expert Panel | 2025-12-16T01:00:00.000Z"
    explanation: >-
      ClinGen's current SCN3B assertion, which is refuted rather than disputed and
      postdates the 2018 reappraisal cited above.
- name: GPD1L variants
  association: Disputed
  relationship_type: DISPUTED
  gene_term:
    preferred_term: GPD1L
    term:
      id: hgnc:28956
      label: GPD1L
  features: >-
    GPD1L is the gene behind the numbered series term Brugada syndrome 2
    (MONDO:0012728) and is one of only four genes present on every Brugada
    multigene test panel surveyed in 2017. It is also the one disputed Brugada
    gene that was found by genetic linkage rather than by candidate-gene
    screening, which is why the reappraisal discusses it separately: all three
    curator teams nonetheless scored it limited, and the expert panel classified
    it disputed. The stated reasons are that the linked region was very large and
    was not comprehensively sequenced, so an alternative gene in the interval was
    never excluded; that the reported variant is now seen in about 1 in 5000
    individuals in public databases; and that no further family has been reported
    since the seminal 2002 publication. Curated here as disputed non-SCN5A
    heterogeneity rather than as a subtype row.
  evidence:
  - reference: PMID:29959160
    reference_title: "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome."
    supports: REFUTE
    directness: DIRECT
    evidence_source: OTHER
    snippet: "Notably, the GPD1L gene received limited evidence classification by all 3 curator teams and a final classification of disputed, despite its identification through the use of genetic linkage."
    explanation: >-
      The expert-panel verdict on GPD1L, and the observation that it holds even
      though this gene was found by linkage rather than by candidate-gene
      screening.
  - reference: PMID:29959160
    reference_title: "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome."
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "the observation that the reported variant in this gene is now recognized to be present in 1/5000 individuals in public databases"
    explanation: >-
      The population-frequency argument against the reported GPD1L allele, the
      same kind of argument that undercut the SCN3B alleles.
  - reference: PMID:29959160
    reference_title: "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome."
    supports: REFUTE
    directness: DIRECT
    evidence_source: OTHER
    snippet: "curators and the expert panel noted the extensive size of the linked genomic region, the select sequencing of only a limited number of genes within this large region"
    explanation: >-
      The specific methodological objection to the GPD1L linkage result: the
      linked interval was large and was not comprehensively sequenced, so an
      alternative causal gene inside it was never excluded.
  - reference: PMID:29959160
    reference_title: "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome."
    supports: REFUTE
    directness: DIRECT
    evidence_source: OTHER
    snippet: "and the absence of any subsequent familial descriptions since the seminal publication in 2002."
    explanation: >-
      Source for this record's statement that no further family has been reported
      since the 2002 seminal publication.
  - reference: PMID:29959160
    reference_title: "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "Only 4 genes were present on all testing panels (SCN5A, GPD1L, CACNA1C, and CACNB2)."
    explanation: >-
      Records how entrenched GPD1L is in clinical Brugada testing, which is why
      the disputed classification is worth stating explicitly here rather than
      leaving the gene unmentioned. Graded INDIRECT because panel membership is
      evidence about testing practice, not about causation.
- name: CACNA1C variants
  association: Disputed
  relationship_type: DISPUTED
  gene_term:
    preferred_term: CACNA1C
    term:
      id: hgnc:1390
      label: CACNA1C
  features: >-
    CACNA1C is the gene behind Brugada syndrome 3 (MONDO:0012742). MONDO puts no
    causal-gene edge on that term directly — the gene is inherited from its second
    parent, MONDO:0700321 CACNA1C-related disorder — so a gene-keyed comparison
    over the numbered Brugada series does not surface it. The Brugada claim rests
    on segregation in only two individuals in two generations, and ClinGen's
    Hereditary Cardiovascular Disease Gene Curation Expert Panel classified
    CACNA1C for Brugada syndrome as disputed in February 2025. This says nothing
    against CACNA1C's definitive disease: Timothy syndrome is a separate entry in
    this KB, and this entry's fever-unmasking node and definitions explicitly
    contrast the Timothy-syndrome fever effect rather than treating CACNA1C as a
    Brugada cause.
  evidence:
  - reference: PMID:29959160
    reference_title: "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome."
    supports: REFUTE
    directness: DIRECT
    evidence_source: OTHER
    snippet: "Three genes were reported with limited segregation in only 2 individuals in 2 generations (CACNA1C, KCNE5, and SCN10A)."
    explanation: >-
      Names CACNA1C among the genes whose founding Brugada reports showed
      segregation in only two individuals, the specific basis for the disputed
      classification.
  - reference: CGGV:assertion_0d869dbe-c00c-4875-93c8-80ba0436b895-2025-02-25T010000.000Z
    reference_title: "CACNA1C / Brugada syndrome (Disputed)"
    supports: REFUTE
    directness: DIRECT
    evidence_source: OTHER
    snippet: "CACNA1C | HGNC:1390 | Brugada syndrome | MONDO:0015263 | AD | Disputed | SOP11 | Hereditary Cardiovascular Disease Gene Curation Expert Panel | 2025-02-25T01:00:00.000Z"
    explanation: >-
      ClinGen's current gene-disease validity assertion for CACNA1C against
      Brugada syndrome, made under SOP11 and dated 2025.
- name: CACNB2 variants
  association: Disputed
  relationship_type: DISPUTED
  gene_term:
    preferred_term: CACNB2
    term:
      id: hgnc:1402
      label: CACNB2
  features: >-
    CACNB2 is the gene behind Brugada syndrome 4 (MONDO:0012743) and, like GPD1L
    and CACNA1C, appears on every Brugada test panel surveyed. It is one of only
    three reported Brugada genes with more than two segregations within a family,
    so its founding evidence was stronger than most; what defeated it was that the
    reappraisal's curators found a reported affected member of that family who did
    not carry the variant, and that no further report supplied enough genetic or
    statistical evidence to move it above the disputed tier. Note that ClinGen's
    current CACNB2 assertion is made against the broader concept
    MONDO:0100547 cardiogenetic disease rather than against Brugada syndrome, and
    is also disputed.
  evidence:
  - reference: PMID:29959160
    reference_title: "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "Only 3 genes (CACNB2, KCNE3, PKP2) were reported to have >2 segregations within a family."
    explanation: >-
      Records that CACNB2's founding report carried more segregations than most
      disputed Brugada genes, which is the reason its disposition needs the
      specific refutation quoted below rather than the generic one.
  - reference: PMID:29959160
    reference_title: "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome."
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "our curators noted a reported affected individual who did not carry the reported variant in CACNB2."
    explanation: >-
      The specific segregation failure in the founding CACNB2 family: an affected
      individual without the variant.
  - reference: CGGV:assertion_1dd59b42-2ed6-4685-b93b-39ba49ece50b-2025-07-22T160000.000Z
    reference_title: "CACNB2 / cardiogenetic disease (Disputed)"
    supports: REFUTE
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "CACNB2 | HGNC:1402 | cardiogenetic disease | MONDO:0100547 | AD | Disputed | SOP11 | Hereditary Cardiovascular Disease Gene Curation Expert Panel | 2025-07-22T16:00:00.000Z"
    explanation: >-
      ClinGen's current CACNB2 assertion. Graded INDIRECT because it is made
      against the broad cardiogenetic-disease concept rather than against Brugada
      syndrome specifically, so it bears on the Brugada claim by inclusion rather
      than directly.
- name: SCN1B variants
  association: Disputed
  relationship_type: DISPUTED
  gene_term:
    preferred_term: SCN1B
    term:
      id: hgnc:10586
      label: SCN1B
  features: >-
    SCN1B encodes the beta-1 subunit of the voltage-gated sodium channel (HGNC
    approved name: sodium voltage-gated channel beta subunit 1) and is the gene
    behind Brugada syndrome 5 (MONDO:0013015) — the sibling claim to
    the SCN3B one this entry already curates, and it failed reappraisal for the
    same reason: the seminal manuscripts reported rare variants in sporadic cases
    only, with no segregation data and no demonstration of rare-variant excess
    against controls. ClinGen's Brugada Syndrome Gene Curation Expert Panel
    classifies SCN1B as disputed for Brugada syndrome. The ClinGen gene-validity
    download committed in this repository (`cache/clingen/gene_validity.csv`) also
    records definitive SCN1B assertions for generalized epilepsy with febrile
    seizures plus and for developmental and epileptic encephalopathy; those are
    different diseases and are not this entry's concern.
  evidence:
  - reference: PMID:29959160
    reference_title: "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome."
    supports: REFUTE
    directness: DIRECT
    evidence_source: OTHER
    snippet: "Seminal manuscripts for 13 of the 19 genes reported rare variants in only sporadic cases with no segregation data or evidence of rare variant excess compared with control subjects (ABCC9, ANK2, CACNA2D1, HCN4, KCND3, KCNH2, KCNJ8, RANGRF, SCN1B, SCN2B, SCN3B, SLMAP, TRPM4)."
    explanation: >-
      Names SCN1B among the genes whose founding reports lacked segregation data
      or rare-variant excess, which is the specific basis for the disputed
      classification here.
  - reference: PMID:29959160
    reference_title: "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome."
    supports: REFUTE
    directness: DIRECT
    evidence_source: OTHER
    snippet: "All other genes (20 of 21) received a final classification of disputed with regard to assertions toward causality for BrS by a clinical domain expert panel."
    explanation: >-
      The expert-panel verdict that places SCN1B, along with every other reported
      non-SCN5A Brugada gene, in the disputed tier.
- name: KCNE3 variants
  association: Disputed
  relationship_type: DISPUTED
  gene_term:
    preferred_term: KCNE3
    term:
      id: hgnc:6243
      label: KCNE3
  features: >-
    KCNE3 is the gene behind Brugada syndrome 6 (MONDO:0013145) and the second of
    the three reported Brugada genes with more than two segregations in a family.
    Four segregations were reported, but the reappraisal judged them insufficient
    in the absence of statistical data, additional families or other supporting
    literature, and ClinGen's Hereditary Cardiovascular Disease Gene Curation
    Expert Panel restated the disputed classification against Brugada syndrome in
    July 2025. Curated here as disputed non-SCN5A heterogeneity rather than as a
    subtype row.
  evidence:
  - reference: PMID:29959160
    reference_title: "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome."
    supports: REFUTE
    directness: DIRECT
    evidence_source: OTHER
    snippet: "Similarly, 4 and 3 segregations were reported in original manuscripts using preconceived candidate gene approaches implicating KCNE3 and PKP2, respectively, but without sufficient statistical data, additional families or supporting evidence in the literature."
    explanation: >-
      Gives the exact reason the KCNE3 claim failed despite four reported
      segregations: no statistical data, no further families, no supporting
      literature.
  - reference: CGGV:assertion_733a6f42-add7-434a-9d4f-a8f11c11c41a-2025-07-22T190000.000Z
    reference_title: "KCNE3 / Brugada syndrome (Disputed)"
    supports: REFUTE
    directness: DIRECT
    evidence_source: OTHER
    snippet: "KCNE3 | HGNC:6243 | Brugada syndrome | MONDO:0015263 | AD | Disputed | SOP11 | Hereditary Cardiovascular Disease Gene Curation Expert Panel | 2025-07-22T19:00:00.000Z"
    explanation: >-
      ClinGen's current gene-disease validity assertion for KCNE3 against Brugada
      syndrome, made under SOP11 and dated 2025.
- name: HCN4 variants
  association: Disputed
  relationship_type: DISPUTED
  gene_term:
    preferred_term: HCN4
    term:
      id: hgnc:16882
      label: HCN4
  features: >-
    HCN4 (HGNC approved name: hyperpolarization activated cyclic nucleotide gated
    potassium channel 4) is the gene behind Brugada syndrome 8 (MONDO:0013148). Its Brugada claim is among the 13 whose seminal manuscripts
    reported rare variants in sporadic cases only, with no segregation data and
    no demonstration of rare-variant excess against controls, and ClinGen's
    Brugada Syndrome Gene Curation Expert Panel classifies it as disputed for
    Brugada syndrome. The same ClinGen download that records the disputed Brugada
    assertion (`cache/clingen/gene_validity.csv`) records a definitive HCN4
    assertion for autosomal dominant sick sinus syndrome 2, a different disease
    that is not curated here.
  evidence:
  - reference: PMID:29959160
    reference_title: "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome."
    supports: REFUTE
    directness: DIRECT
    evidence_source: OTHER
    snippet: "Seminal manuscripts for 13 of the 19 genes reported rare variants in only sporadic cases with no segregation data or evidence of rare variant excess compared with control subjects (ABCC9, ANK2, CACNA2D1, HCN4, KCND3, KCNH2, KCNJ8, RANGRF, SCN1B, SCN2B, SCN3B, SLMAP, TRPM4)."
    explanation: >-
      Names HCN4 among the genes whose founding reports lacked segregation data or
      rare-variant excess, which is the specific basis for the disputed
      classification here.
  - reference: PMID:29959160
    reference_title: "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome."
    supports: REFUTE
    directness: DIRECT
    evidence_source: OTHER
    snippet: "All other genes (20 of 21) received a final classification of disputed with regard to assertions toward causality for BrS by a clinical domain expert panel."
    explanation: >-
      The expert-panel verdict that places HCN4, along with every other reported
      non-SCN5A Brugada gene, in the disputed tier.
- name: KCND3 variants
  association: Disputed
  relationship_type: DISPUTED
  gene_term:
    preferred_term: KCND3
    term:
      id: hgnc:6239
      label: KCND3
  features: >-
    KCND3 (HGNC approved name: potassium voltage-gated channel subfamily D member
    3, alias Kv4.3) is the gene behind Brugada syndrome 9 (MONDO:0014621). Its
    Brugada claim is among the 13 whose seminal manuscripts reported rare variants
    in sporadic cases only, with no segregation data and no demonstration of
    rare-variant excess against controls, and ClinGen's Brugada Syndrome Gene
    Curation Expert Panel classifies it as disputed. Curated here as disputed
    non-SCN5A heterogeneity rather than as a subtype row.
  evidence:
  - reference: PMID:29959160
    reference_title: "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome."
    supports: REFUTE
    directness: DIRECT
    evidence_source: OTHER
    snippet: "Seminal manuscripts for 13 of the 19 genes reported rare variants in only sporadic cases with no segregation data or evidence of rare variant excess compared with control subjects (ABCC9, ANK2, CACNA2D1, HCN4, KCND3, KCNH2, KCNJ8, RANGRF, SCN1B, SCN2B, SCN3B, SLMAP, TRPM4)."
    explanation: >-
      Names KCND3 among the genes whose founding reports lacked segregation data
      or rare-variant excess, which is the specific basis for the disputed
      classification here.
  - reference: PMID:29959160
    reference_title: "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome."
    supports: REFUTE
    directness: DIRECT
    evidence_source: OTHER
    snippet: "All other genes (20 of 21) received a final classification of disputed with regard to assertions toward causality for BrS by a clinical domain expert panel."
    explanation: >-
      The expert-panel verdict that places KCND3, along with every other reported
      non-SCN5A Brugada gene, in the disputed tier.
treatments:
- name: Implantable cardioverter-defibrillator placement
  description: >-
    Device therapy for prevention of sudden cardiac death in high-risk Brugada
    syndrome, especially after malignant ventricular arrhythmia, syncope with
    high-risk features, or recurrent ventricular fibrillation.
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  evidence:
  - reference: PMID:39800093
    reference_title: "Epicardial substrate ablation in patients with symptomatic Brugada syndrome: An updated systematic review and single-arm meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although implantable cardioverter-defibrillators (ICDs) and quinidine are primary treatments, recurrent BrS-triggered ventricular arrhythmias can persist."
    explanation: Supports ICD placement as a primary established treatment in symptomatic or high-risk Brugada syndrome.
  target_mechanisms:
  - target: Malignant Ventricular Tachyarrhythmia
    treatment_effect: MODULATES
    description: >-
      ICDs detect and terminate ventricular fibrillation and polymorphic
      ventricular tachycardia with defibrillation shocks, preventing sudden
      cardiac death without altering the underlying arrhythmogenic substrate.
    evidence:
    - reference: PMID:39800093
      reference_title: "Epicardial substrate ablation in patients with symptomatic Brugada syndrome: An updated systematic review and single-arm meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Although implantable cardioverter-defibrillators (ICDs) and quinidine are primary treatments, recurrent BrS-triggered ventricular arrhythmias can persist."
      explanation: >-
        The meta-analysis identifies ICDs as primary treatment for
        Brugada-triggered ventricular arrhythmias; the cached abstract does not
        describe the device's detection-and-shock mechanism.
- name: Quinidine
  description: >-
    Quinidine is used as antiarrhythmic pharmacotherapy for suppression of
    recurrent ventricular arrhythmia and electrical storm in Brugada syndrome,
    particularly when ICD therapy alone is insufficient or when ablation is not
    immediately available.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: quinidine
      term:
        id: CHEBI:28593
        label: quinidine
  evidence:
  - reference: PMID:40750064
    reference_title: Theory and practice of present clinical use of Quinidine in the management of cardiac arrhythmias.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Paradoxically, this decline in use occurred alongside accumulating evidence supporting quinidine's therapeutic benefit in managing rare, life-threatening ventricular arrhythmias occurring in patients with no organic heart disease (Idiopathic ventricular fibrillation, Brugada syndrome, Early repolarization syndrome, Short QT syndrome, Multifocal ectopic Purkinje-related premature contractions), as well as in those with organic heart disease involving the Purkinje network (acute myocardial infarction and hypertrophic cardiomyopathy)."
    explanation: Supports quinidine as a specifically recognized antiarrhythmic option for Brugada syndrome and related idiopathic ventricular fibrillation syndromes.
  target_mechanisms:
  - target: Reduced Depolarization Reserve
    treatment_effect: MODULATES
    description: >-
      Quinidine blocks the transient outward potassium current (Ito) in
      epicardial RVOT cardiomyocytes, partially restoring the balance between
      inward and outward currents and reducing the action potential notch that
      precipitates phase-2 reentry.
    evidence:
    - reference: PMID:27803673
      reference_title: "Electrophysiological Mechanisms of Brugada Syndrome: Insights from Pre-clinical and Clinical Studies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Thus, either reduced Ito or increased ICa could compensate for the reduced sodium current, in turn reducing the degree of ST segment elevation."
      explanation: >-
        The mechanistic review supports reduced Ito as compensation for reduced
        sodium current. Together with the treatment-level quinidine evidence,
        this partially supports the inferred Ito-blocking mechanism.
- name: Epicardial substrate ablation
  description: >-
    Epicardial ablation of the Brugada arrhythmogenic substrate is an
    increasingly used option for symptomatic patients with recurrent BrS-triggered
    ventricular arrhythmias despite ICD therapy and/or quinidine.
  treatment_term:
    preferred_term: epicardial ablation
    term:
      id: NCIT:C157843
      label: Epicardial Ablation
  evidence:
  - reference: PMID:39800093
    reference_title: "Epicardial substrate ablation in patients with symptomatic Brugada syndrome: An updated systematic review and single-arm meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although implantable cardioverter-defibrillators (ICDs) and quinidine are primary treatments, recurrent BrS-triggered ventricular arrhythmias can persist. In this setting, epicardial substrate ablation has emerged as a promising alternative for symptomatic patients."
    explanation: Supports epicardial substrate ablation as a treatment option for symptomatic patients with recurrent arrhythmias despite standard therapy.
  - reference: PMID:39800093
    reference_title: "Epicardial substrate ablation in patients with symptomatic Brugada syndrome: An updated systematic review and single-arm meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pooled analysis demonstrated resolution of the type 1 pattern in 91% of the cases"
    explanation: Supports mechanistic and electrocardiographic efficacy of epicardial substrate ablation in symptomatic Brugada syndrome cohorts.
  target_mechanisms:
  - target: Current-Load Mismatch at RVOT Substrate
    treatment_effect: MODULATES
    description: >-
      Epicardial ablation destroys the fibrotic-fatty RVOT epicardial substrate
      responsible for abnormal conduction and the current-load mismatch that
      sustains phase-2 reentry, eliminating the anatomic basis for arrhythmia
      inducibility.
    evidence:
    - reference: PMID:39800093
      reference_title: "Epicardial substrate ablation in patients with symptomatic Brugada syndrome: An updated systematic review and single-arm meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In this setting, epicardial substrate ablation has emerged as a promising alternative for symptomatic patients."
      explanation: >-
        The meta-analysis supports epicardial substrate ablation in symptomatic
        Brugada syndrome, but its abstract does not isolate elimination of the
        current-load-mismatch substrate as the operative mechanism.
computational_models:
- name: Subcellular sodium-channel myocardial strand model
  description: >-
    A one-dimensional strand of 300 human epicardial ventricular myocytes for
    studying how subcellular sodium-channel distribution changes action-potential
    morphology and propagation. Each cell is divided into lateral and pre- and
    post-junctional membrane segments, represented by a modified O'Hara-Rudy
    dynamic model with ten Tusscher-Panfilov fast sodium current and an
    experimentally based rapid delayed-rectifier potassium current. Cells are
    coupled through gap junctions and ephaptic interactions. The disease-like
    manipulation reduces lateral-membrane sodium conductance while retaining
    junctional sodium conductance.
  model_type: KINETIC
  repository_url: https://github.com/92tsumoto/BrS-P2R-strand-ORd2011model-withTNNP_INa-FT_IKr/tree/90962d4c159d5b12133d99cb0818c84c6746a013
  model_id: 1D_EF_mORD2
  base_model: Modified O'Hara-Rudy dynamic 2011 human ventricular model with ten Tusscher-Panfilov fast INa and experimental IKr
  model_software: C/Autotools; Intel C Compiler, Intel MKL/PARDISO, and Intel OpenMP (original configuration)
  model_format: C source, Autotools build files, and positional text input
  publication: PMID:33203944
  variables:
  - name: Lateral-membrane sodium conductance fraction
    description: Fast and late lateral-membrane sodium conductance expressed as a percentage of control.
  - name: Action-potential membrane voltage
    description: Membrane-potential trajectory for each modeled cell and membrane segment.
  - name: Conduction velocity
    description: >-
      Propagation velocity along the myocardial strand in centimeters per
      second, derived in the publication from activation-time outputs rather
      than emitted directly by the code.
  modeled_mechanisms:
  - target: Reduced Depolarization Reserve
    relationship: PERTURBS
    description: >-
      The model directly reduces lateral-membrane sodium conductance and measures
      the resulting action-potential changes, rather than reproducing the full
      genetically and structurally heterogeneous Brugada mechanism.
    fidelity: MODERATE
    limitations: >-
      Sodium-channel reduction is prescribed phenomenologically rather than
      generated by an SCN5A allele, trafficking defect, or patient-calibrated
      expression state. The model does not represent broader calcium- or
      potassium-channel causes of reduced depolarization reserve.
    readouts:
    - name: Action-potential dome morphology
      target: Reduced Depolarization Reserve
      description: >-
        Progressive lateral sodium-channel reduction produces notch-and-dome,
        delayed-dome, and loss-of-dome action potentials.
      direction: ALTERED
      evidence:
      - reference: PMID:33203944
        reference_title: Specific decreasing of Na(+) channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome.
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: >-
          Reducing Na+ channel expression in the lateral membrane of each
          myocyte caused not only the notch-and-dome but also loss-of-dome type
          action potentials and slowed conduction, both of which are typically
          observed in BrS patients.
        explanation: The strand simulation reports the expected action-potential response to its sodium-conductance perturbation.
    evidence:
    - reference: PMID:33203944
      reference_title: Specific decreasing of Na(+) channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Reducing Na+ channel expression in the lateral membrane of each myocyte
        caused not only the notch-and-dome but also loss-of-dome type action
        potentials and slowed conduction, both of which are typically observed
        in BrS patients.
      explanation: The paper identifies the manipulated sodium-channel process and its electrophysiologic outputs.
  - target: RVOT Conduction Slowing
    relationship: PARTIALLY_RECAPITULATES
    description: >-
      Reduced lateral sodium conductance lowers modeled upstroke velocity and
      strand conduction velocity, recapitulating the conduction-slowing component
      of the Brugada substrate.
    fidelity: MODERATE
    limitations: >-
      This is a homogeneous one-dimensional generic epicardial ventricular strand,
      not an anatomically reconstructed RVOT. It omits patient-specific geometry,
      fibrosis, fiber organization, ECG leads, and clinical conduction maps.
    readouts:
    - name: Conduction velocity
      target: RVOT Conduction Slowing
      description: >-
        Conduction velocity falls as lateral-membrane sodium conductance is
        reduced from control to complete loss.
      direction: DECREASED
      evidence:
      - reference: PMID:33203944
        reference_title: Specific decreasing of Na(+) channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome.
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: >-
          CVs at 100%gNa,LM, 35%gNa,LM, 7%gNa,LM and 0%gNa,LM were 71.4,
          53.6, 33.3, and 25.0 cm/s, respectively (see Table 1).
        explanation: The full-text figure caption provides the quantitative conduction-velocity response.
    evidence:
    - reference: PMID:33203944
      reference_title: Specific decreasing of Na(+) channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Reducing Na+ channel expression in the lateral membrane of each myocyte
        caused not only the notch-and-dome but also loss-of-dome type action
        potentials and slowed conduction, both of which are typically observed
        in BrS patients.
      explanation: The primary report directly identifies slowed propagation as a model output.
  evidence:
  - reference: PMID:33203944
    reference_title: Specific decreasing of Na(+) channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      We constructed in silico human ventricular myocardial strand and ring
      models, and examined whether the Na+ channel expression changes in each
      myocyte cause the phase-2 reentry in BrS.
    explanation: The publication defines the human ventricular strand model and its Brugada perturbation.
  findings:
  - statement: >-
      In the homogeneous-conductance comparison, reducing lateral-membrane
      sodium conductance from 100% to 0% lowers conduction velocity from 71.4
      to 25.0 cm/s.
    evidence:
    - reference: PMID:33203944
      reference_title: Specific decreasing of Na(+) channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        CVs at 100%gNa,LM, 35%gNa,LM, 7%gNa,LM and 0%gNa,LM were 71.4,
        53.6, 33.3, and 25.0 cm/s, respectively (see Table 1).
      explanation: The paper reports a monotonic decrease across its four homogeneous conductance settings.
  notes: >-
    The repository is pinned at commit
    90962d4c159d5b12133d99cb0818c84c6746a013 and has no release, CI,
    container, or dependency lock. COPYING declares GPL-3.0, but
    src/pardiso_mat.c carries an Intel Confidential notice that restricts use,
    copying, and distribution; the effective reuse and redistribution status is
    therefore ambiguous. The checked-in build targets legacy Intel C Compiler,
    MKL/PARDISO, and OpenMP paths and flags. It did not compile unmodified during
    curator testing on ARM macOS. The fixed-step explicit-Euler simulation uses
    a 1-microsecond step for 30 beats. Its only sample input is stale: for the
    supplied one-dataset, 43-state configuration, the parser reads 83 numeric
    fields whereas check_test/in supplies 82, shifting later values and
    preventing a faithful run. No paper-scenario manifest, expected outputs, or
    automated tests are supplied. The code emits voltage and ionic traces plus
    activation times but does not directly calculate CV; nai_data.out and
    ki_data.out are also mislabeled relative to their written state indices.
    The article is CC BY 4.0. The model was compared qualitatively with prior
    mouse and human electrophysiology, but it was not fitted to or independently
    validated in a Brugada patient cohort.
- name: Spatially heterogeneous sodium-channel myocardial ring model
  description: >-
    A one-dimensional ring of 600 human epicardial ventricular myocytes using
    the same modified O'Hara-Rudy ionic model, segmented cell membranes, gap
    junctions, and ephaptic coupling as the companion strand model. Two ring
    regions are assigned different, markedly reduced lateral-membrane sodium
    conductances to test whether spatial heterogeneity converts phase-2 reentry
    into intermittent or persistent circulating reentrant excitation.
  model_type: KINETIC
  repository_url: https://github.com/92tsumoto/BrS-P2R-ring-ORd2011model-withTNNP_INa-FT_IKr/tree/0a6aece22925ca48430d775589547bbfbf9e0ff0
  model_id: 1D_EFring_mORD2
  base_model: Modified O'Hara-Rudy dynamic 2011 human ventricular model with ten Tusscher-Panfilov fast INa and experimental IKr
  model_software: C/Autotools; Intel C Compiler, Intel MKL/PARDISO, and Intel OpenMP (original configuration)
  model_format: C source, Autotools build files, and positional text input
  publication: PMID:33203944
  variables:
  - name: Regional lateral-membrane sodium conductance fractions
    description: Separately imposed percentages of control lateral sodium conductance in the two ring regions.
  - name: Action-potential propagation pattern
    description: >-
      Spatiotemporal membrane-voltage propagation around the ring; block,
      phase-2 reentry, and circulating reentry are interpreted from the traces
      rather than classified directly by the code.
  modeled_mechanisms:
  - target: Malignant Ventricular Tachyarrhythmia
    relationship: PARTIALLY_RECAPITULATES
    description: >-
      The heterogeneous ring produces phase-2-reentry-mediated circulating
      excitation, representing a reduced tissue-scale mechanism for Brugada
      reentrant tachyarrhythmia.
    fidelity: LOW
    limitations: >-
      The 600-cell one-dimensional ring is not an RVOT or whole-heart geometry
      and cannot reproduce polymorphic VT, ventricular fibrillation, surface ECG,
      hemodynamics, or patient outcomes. Reentry depends on imposed and locally
      extreme sodium-conductance heterogeneity rather than measured patient
      tissue or a disease genotype.
    readouts:
    - name: Phase-2-reentry-mediated reentrant arrhythmia
      target: Malignant Ventricular Tachyarrhythmia
      description: >-
        Spatially heterogeneous lateral sodium-channel reduction produces
        intermittent or persistent unidirectional circulating excitation.
      direction: INCREASED
      evidence:
      - reference: PMID:33203944
        reference_title: Specific decreasing of Na(+) channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome.
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: >-
          Furthermore, the selective reduction in Na+ channels on the lateral
          membrane of each myocyte together with spatial tissue heterogeneity of
          Na+ channel expression caused the phase-2 reentry and phase-2
          reentry-mediated reentrant arrhythmias.
        explanation: The ring simulation directly produces its reduced reentrant-arrhythmia readout.
    evidence:
    - reference: PMID:33203944
      reference_title: Specific decreasing of Na(+) channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Furthermore, the selective reduction in Na+ channels on the lateral
        membrane of each myocyte together with spatial tissue heterogeneity of
        Na+ channel expression caused the phase-2 reentry and phase-2
        reentry-mediated reentrant arrhythmias.
      explanation: The publication identifies sodium-channel heterogeneity as necessary for the modeled reentry.
  evidence:
  - reference: PMID:33203944
    reference_title: Specific decreasing of Na(+) channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      We constructed in silico human ventricular myocardial strand and ring
      models, and examined whether the Na+ channel expression changes in each
      myocyte cause the phase-2 reentry in BrS.
    explanation: The publication defines the human ventricular ring model and its Brugada perturbation.
  findings:
  - statement: >-
      Reentry occurred mainly when region B lateral sodium conductance was below
      5% of control and region A was between 5% and 10%, underscoring dependence
      on an extreme imposed spatial gradient.
    evidence:
    - reference: PMID:33203944
      reference_title: Specific decreasing of Na(+) channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        This result indicates that the P2R-mediated reentry occurred mostly when
        the %gNa,LM in the region B was reduced to < 5% and the %gNa,LM in the
        region A was in the 5 ~ 10% range (Fig. 6C, magenta region).
      explanation: The phase diagram identifies the parameter region supporting ring reentry.
  notes: >-
    The repository is pinned at commit
    0a6aece22925ca48430d775589547bbfbf9e0ff0 and has no release, CI,
    container, dependency lock, or sample input. COPYING declares GPL-3.0, but
    src/pardiso_mat.c carries an Intel Confidential notice that restricts use,
    copying, and distribution; the effective reuse and redistribution status is
    therefore ambiguous. The checked-in build targets legacy Intel C Compiler,
    MKL/PARDISO, and OpenMP paths and flags and did not compile unmodified during
    curator testing on ARM macOS. The fixed-step explicit-Euler simulation uses
    a 1-microsecond step for 30 beats, nominally 30 million steps. The repository
    supplies no paper-figure parameter manifest, golden output, analysis script,
    or automated test. It emits voltage and current traces but does not directly
    label phase-2 reentry, reentrant arrhythmia, or the published phase diagram;
    an auxiliary cleft-potential output also omits the closing ring junction.
    The article is CC BY 4.0. This is a hypothesis-driven mechanism model, not an
    allele-specific, anatomically personalized, or clinically predictive
    ventricular simulation.
animal_models:
- name: Scn3b-null mouse (Scn3b-/-)
  species: Mouse
  genotype: Scn3b homozygous knockout
  publication: PMID:19796257
  genes:
  - preferred_term: SCN3B
    term:
      id: hgnc:20665
      label: SCN3B
  description: >-
    Germline Scn3b knockout mouse, the only in vivo model of the gene behind
    Brugada syndrome 7. Scn3b transcript is absent from the atria and the beta-3
    protein from cardiac myocytes, while Scn1b and Scn5a transcript levels are
    unchanged, so the phenotype is attributable to loss of beta-3 specifically.
    The reported cardiac phenotype spans both chambers, in two papers from the
    same group: sinus bradycardia, P-wave and PR prolongation, prolonged sinus
    node recovery, atrioventricular dissociation and inducible atrial
    tachyarrhythmia, and separately reduced peak sodium current in ventricular
    myocytes with shortened ventricular effective refractory periods and
    inducible monomorphic or polymorphic ventricular tachycardia.
  evidence:
  - reference: PMID:19796257
    reference_title: Scn3b knockout mice exhibit abnormal sino-atrial and cardiac conduction properties.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Scn3b mRNA was expressed in the atria of WT but not Scn3b(-/-) hearts."
    explanation: >-
      Confirms the model is a true null for the gene of interest, which is what
      makes it informative about the consequences of losing beta-3.
  modeled_mechanisms:
  - target: Reduced Depolarization Reserve
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Complete loss of the beta-3 subunit reduces peak sodium current density
      measured directly in ventricular myocytes and slows cardiac conduction in
      vivo, matching the direction of the reduced sodium current that SCN3B
      variants produce in transfected cells.
    limitations: >-
      The model is a homozygous null, whereas the reported human variants are
      heterozygous missense or single-codon deletions, so it speaks to complete
      loss of beta-3 rather than to the alleles actually found in patients, and
      those alleles are what the disputed classification turns on. Murine
      ventricular repolarization also differs substantially from human, the
      standing caveat for any mouse model of a repolarization-dependent
      arrhythmia syndrome.
    readouts:
    - name: Atrioventricular conduction time (PR interval)
      target: Reduced Depolarization Reserve
      direction: INCREASED
      interpretation: >-
        PR prolongation is the in vivo correlate of reduced sodium-channel
        availability, the same direction of effect reported for SCN3B variants
        in heterologous expression.
      evidence:
      - reference: PMID:19796257
        reference_title: Scn3b knockout mice exhibit abnormal sino-atrial and cardiac conduction properties.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Lead I electrocardiograms from Scn3b(-/-) mice showed slower heart rates, longer P wave durations and prolonged PR intervals than WT hearts."
        explanation: Reports the conduction measurements behind this readout.
    - name: Atrial arrhythmia inducibility on burst pacing
      target: Reduced Depolarization Reserve
      direction: INCREASED
      interpretation: >-
        Inducible atrial tachyarrhythmia is the arrhythmic counterpart of
        reduced sodium-channel availability in this chamber; the companion study
        reports the ventricular counterpart separately.
      evidence:
      - reference: PMID:19796257
        reference_title: Scn3b knockout mice exhibit abnormal sino-atrial and cardiac conduction properties.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Atrial burst pacing protocols induced atrial tachycardia and fibrillation in all Scn3b(-/-) but hardly any WT hearts."
        explanation: Reports the inducible atrial arrhythmia behind this readout.
    evidence:
    - reference: PMID:19796257
      reference_title: Scn3b knockout mice exhibit abnormal sino-atrial and cardiac conduction properties.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These findings demonstrate, for the first time, that a deficiency in Scn3b results in significant atrial electrophysiological and intracardiac conduction abnormalities, complementing the changes in ventricular electrophysiology reported on an earlier occasion."
      explanation: >-
        Supports treating the model as informative for the depolarization-reserve
        node, and points to the companion ventricular study.
    - reference: PMID:19351516
      reference_title: Scn3b knockout mice exhibit abnormal ventricular electrophysiological properties.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The whole-cell patch-clamp technique applied to ventricular myocytes isolated from Scn3b(-/-) hearts demonstrated reduced peak Na(+) current densities and inactivation curves that were shifted in the negative direction, relative to those shown in WT myocytes."
      explanation: >-
        Measures the reduced sodium current directly in ventricular myocytes,
        which is what makes this model informative for the depolarization-reserve
        node rather than only for atrial conduction.
  - target: Malignant Ventricular Tachyarrhythmia
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Beta-3 loss produces an inducible ventricular arrhythmic phenotype with
      shortened ventricular effective refractory periods, which the authors read
      as resembling Scn5a heterozygous hearts.
    limitations: >-
      The arrhythmia is induced by programmed electrical stimulation in a
      Langendorff-perfused heart rather than arising spontaneously, and it is not
      reported as arising from a right-ventricular outflow-tract substrate with
      the epicardial repolarization heterogeneity that characterises human
      Brugada syndrome. As above, the genotype is a homozygous null rather than
      the heterozygous human alleles.
    readouts:
    - name: Inducible ventricular tachycardia on programmed stimulation
      target: Malignant Ventricular Tachyarrhythmia
      direction: INCREASED
      interpretation: >-
        Establishes that loss of beta-3 alone is sufficient for ventricular
        arrhythmic vulnerability in an intact heart.
      evidence:
      - reference: PMID:19351516
        reference_title: Scn3b knockout mice exhibit abnormal ventricular electrophysiological properties.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Bipolar electrogram and monophasic action potential recordings from the ventricles of Langendorff-perfused Scn3b(-/-) hearts demonstrated significantly shorter ventricular effective refractory periods (VERPs), larger ratios of electrogram duration obtained at the shortest and longest S(1)-S(2) intervals, and ventricular tachycardias (VTs) induced by programmed electrical stimulation."
        explanation: Reports the inducible ventricular tachycardia behind this readout.
    evidence:
    - reference: PMID:19351516
      reference_title: Scn3b knockout mice exhibit abnormal ventricular electrophysiological properties.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Together, these findings associate the lack of the Scn3b gene with arrhythmic tendencies in intact perfused hearts and electrophysiological features similar to those in Scn5a(+/-) hearts."
      explanation: >-
        Supports treating the model as informative for the ventricular
        arrhythmia node, by explicit comparison with the canonical
        sodium-channel arrhythmia model.
differential_diagnoses:
- name: Brugada phenocopy
  description: >-
    A type 1 or type 2 Brugada ECG pattern in the right precordial leads that is
    produced by an identifiable, reversible clinical condition in a person who does
    not have congenital Brugada syndrome. Reported provoking conditions include
    hyperkalemia and other electrolyte or metabolic derangements (hyponatremia,
    hypokalemia, acidosis), myocardial ischemia and acute coronary occlusion,
    pulmonary embolism, mechanical compression of the right ventricular outflow
    tract (including pectus excavatum), acute pericarditis, septic shock,
    adjacent pleural-space infection, recreational-drug intoxication, and
    inappropriate ECG filter settings. The term itself was coined for the
    acquired Brugada-like pattern of propofol infusion syndrome (curated
    separately as Propofol_Infusion_Syndrome), yet the classification that
    adopted the term lists propofol among the sodium-channel-blocking drugs it
    says mostly cannot be considered phenocopies, so whether that syndrome's
    ECG change is a phenocopy is unsettled. The ECG
    pattern itself does not separate the two: in a blinded study, international
    Brugada experts classified phenocopy and syndrome tracings only marginally
    better than chance. The distinction matters for management, because a
    phenocopy resolves when its cause is corrected and does not warrant the
    long-term risk stratification, drug restrictions or defibrillator decisions
    that follow a diagnosis of Brugada syndrome.
  phenotypes:
  - name: Type 1 coved ST-segment elevation
    phenotype_term:
      preferred_term: Type 1 coved ST-segment elevation
      term:
        id: HP:6000984
        label: Coved type ST segment elevation
  - name: Type 2 saddleback ST-segment elevation
    phenotype_term:
      preferred_term: Type 2 saddleback ST-segment elevation
      term:
        id: HP:6000985
        label: Saddle-back type ST segment elevation
  distinguishing_features:
  - An identifiable reversible provoking condition present when the pattern is
    recorded (for example serum potassium above about 6.5 mmol/L in
    hyperkalemia-induced phenocopy)
  - Resolution of the Brugada ECG pattern once the provoking condition is corrected,
    typically within hours for hyperkalemia
  - A negative provocative challenge with a sodium channel blocker (ajmaline,
    procainamide or flecainide) after the provoking condition has resolved; this is
    a mandatory criterion for a class A phenocopy
  - Absence of a pathogenic variant in Brugada syndrome genes, with the caveat that
    most clinically confirmed Brugada syndrome is itself genotype-negative, so a
    negative test supports but does not establish a phenocopy
  - Absence of a family history of sudden cardiac death; a ventricular arrhythmia
    at presentation does not exclude a phenocopy, since a class Ic overdose
    case reported as a drug-induced phenocopy presented with ventricular
    fibrillation
  evidence:
  - reference: PMID:23094876
    reference_title: "Brugada phenocopy: new terminology and proposed classification."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: >-
      The term Brugada phenocopy is proposed to describe conditions that induce
      Brugada-like ECG manifestations in patients without true Brugada syndrome.
    explanation: >-
      The founding definition of the term, which frames the phenocopy as a
      differential of the syndrome rather than a form of it.
  - reference: PMID:23094876
    reference_title: "Brugada phenocopy: new terminology and proposed classification."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      Riera et al. introduced the term "Brugada phenocopy" to describe an
      acquired Brugada-like ECG pattern in the setting of propofol infusion
      syndrome.
    explanation: >-
      Records that the phenocopy term originated with propofol infusion
      syndrome, crediting the earlier paper that coined it.
  - reference: PMID:20544610
    reference_title: Propofol infusion syndrome and Brugada syndrome electrocardiographic phenocopy.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      This anesthetic drug may cause a rare condition named propofol infusion
      syndrome, characterized by unexplained lactic acidosis, lipemia,
      rhabdomyolysis, cardiovascular collapse and Brugada-like
      electrocardiographic pattern or Brugada electrocardiographic phenocopy
      changes following high-dose propofol infusion over prolonged periods of
      time.
    explanation: >-
      The paper that introduced the term, describing the Brugada-like pattern
      as one feature of propofol infusion syndrome after high-dose, prolonged
      infusion.
  - reference: PMID:23094876
    reference_title: "Brugada phenocopy: new terminology and proposed classification."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: >-
      Group 1 is composed of tricyclic antidepressants (amitriptyline,
      clomipramine, desipramine, and nortriptyline), antipsychotic agents
      (loxapine and trifluoperazine), lithium, bupivacaine, propofol,
      acetylcholine, alcohol, cocaine, and ergonovine.
    explanation: >-
      Places propofol in the classification's Group 1 drugs, which the same
      paper says act mainly by sodium channel blockade.
  - reference: PMID:23094876
    reference_title: "Brugada phenocopy: new terminology and proposed classification."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: >-
      Consequently, the Group 1 drugs for the most part cannot be considered
      Brugada phenocopies.
    explanation: >-
      The classification's conclusion on Group 1 drugs, which includes
      propofol; supports the description's statement that the syndrome the
      term was coined for sits awkwardly inside the category.
  - reference: PMID:24669289
    reference_title: "Brugada phenocopy: A new electrocardiogram phenomenon."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      However, BrP are elicited by various underlying clinical conditions such as
      myocardial ischemia, pulmonary embolism, electrolyte abnormalities, or poor
      ECG filters. Upon resolution of the inciting underlying pathological
      condition, the BrP ECG subsequently normalizes.
    explanation: >-
      Names the provoking conditions and the reversibility that separates a
      phenocopy from the syndrome.
  - reference: PMID:26498159
    reference_title: "Expert cardiologists cannot distinguish between Brugada phenocopy and Brugada syndrome electrocardiogram patterns."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The overall accuracy was 53 ± 33% for all cases.
    explanation: >-
      Ten international Brugada experts reading blinded tracings could not
      reliably separate phenocopy from syndrome ECGs, so the distinction has to
      rest on clinical context and follow-up testing rather than ECG morphology.
  - reference: PMID:26922708
    reference_title: "Brugada syndrome and Brugada phenocopy. The importance of a differential diagnosis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      They form a group of heterogeneous conditions that are perhaps the most
      difficult to differentiate from true congenital BrS due to identical ECG
      patterns
    explanation: >-
      States why this is the hardest differential for Brugada syndrome.
  - reference: PMID:31078108
    reference_title: "Brugada phenocopy: Mechanisms, diagnosis, and implications."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      It has the same pattern classification of Brugada syndrome (i.e., types 1 and
      2), but differs substantially regarding etiology and prognosis.
    explanation: >-
      Supports the prognostic difference that makes the differential clinically
      consequential.
  - reference: PMID:25201124
    reference_title: "Brugada phenocopy: morphological classification and importance of provocative testing."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: >-
      Class A includes BrP that have met all mandatory diagnostic criteria
      including negative provocative challenge with a sodium channel blocker.
    explanation: >-
      Establishes the negative sodium-channel-blocker challenge as a mandatory
      criterion for a fully confirmed (class A) phenocopy.
  - reference: PMID:29397883
    reference_title: "Relation of the Brugada Phenocopy to Hyperkalemia (from the International Registry on Brugada Phenocopy)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The Brugada ECG pattern appears to occur at high serum potassium
      concentrations (>6.5 mmol/L). The ECG normalizes within hours of correcting
      the electrolyte imbalance. Importantly, hyperkalemia-induced BrP has not been
      associated with sudden cardiac death or ventricular arrhythmia.
    explanation: >-
      Registry series of 27 cases characterizing hyperkalemia as a phenocopy
      trigger: the potassium threshold, the time course of resolution, and the
      benign arrhythmic outcome.
  - reference: PMID:29397883
    reference_title: "Relation of the Brugada Phenocopy to Hyperkalemia (from the International Registry on Brugada Phenocopy)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      In 7 cases (26%), provocative testing using sodium channel blockers was
      performed, and all failed to reproduce a BrS ECG pattern (BrP class A).
    explanation: >-
      Shows the negative provocative challenge that separates the phenocopy from
      unmasked Brugada syndrome in practice.
  - reference: PMID:41721816
    reference_title: "Propafenone Overdose Presenting With Brugada Phenocopy, QRS Widening, and Ventricular Fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      At near 1-year follow-up, standard and high right-precordial ECGs (V1′, V2′
      and V1″, V2″) again showed no Brugada-type morphology (Figure 3), confirming
      sustained resolution and supporting a purely drug-induced BrP.
    explanation: >-
      A single case labelled as a drug-induced phenocopy after a class Ic
      overdose, resting on sustained ECG normalization, normal cardiac MRI and no
      family history. No sodium-channel-blocker challenge was reported, so on the
      classification in PMID:25201124 it would not meet class A criteria; see
      notes.
  - reference: PMID:29899727
    reference_title: "Flecainide-Induced Brugada Syndrome in a Patient With Skeletal Muscle Sodium Channelopathy: A Case Report With Critical Therapeutical Implications and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      After an appropriate pharmacological wash-out, ajmaline challenge was
      performed and resulted positive for the appearance of Brugada pattern type I
    explanation: >-
      The counter-example to the propafenone case: a flecainide-provoked type 1
      pattern that resolved on withdrawal but was then reproduced by ajmaline
      after washout, leading to a diagnosis of Brugada syndrome rather than a
      phenocopy. Reversibility alone did not establish a phenocopy here; the
      post-washout provocative test decided it.
  - reference: PMID:28958975
    reference_title: Not All Brugada Electrocardiogram Patterns are Brugada Syndrome or Brugada Phenocopy.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The term Brugada phenocopies does not cover abnormal electrocardiogram
      patterns that are induced by sodium channel blockers (2). Thus, overdose
      using propafenone would not be considered Brugada phenocopies and instead,
      may be classified as an "acquired sodium channel dysfunction".
    explanation: >-
      The classification's own authors exclude sodium-channel-blocker patterns
      from the phenocopy category and name a separate category for them, which is
      why a drug-provoked pattern is recorded here as contested rather than as a
      phenocopy trigger.
  - reference: PMID:28958975
    reference_title: Not All Brugada Electrocardiogram Patterns are Brugada Syndrome or Brugada Phenocopy.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Although the effects of large doses have not been systematically
      investigated, we suspect that overdoses of propafenone may induce
      artificial sodium channel dysfunction even without genetic predisposition,
      causing a Brugada electrocardiogram pattern.
    explanation: >-
      The same letter accepts that an overdose can produce the pattern in someone
      with no genetic predisposition, which is the substrate-free mechanism the
      phenocopy label describes. The disagreement with the case-report literature
      is therefore about which name to use, not about what happened.
  - reference: PMID:28381391
    reference_title: "Brugada-Phenocopy Induced by Propafenone Overdose and Successful Treatment: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Absence of symptoms and documented ventricular tachycardia, negative
      challenge test, and a negative family history demonstrated that the Brugada
      phenocopy was a transient finding in this case and related to propafenone
      intoxication.
    explanation: >-
      A class Ic overdose in which the discriminating test was actually done and
      was negative, so a drug-provoked pattern can satisfy the class A criterion.
      PMID:28958975 is the classification authors' reply to this case, refusing
      the phenocopy label even so.
  - reference: PMID:28381391
    reference_title: "Brugada-Phenocopy Induced by Propafenone Overdose and Successful Treatment: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Ajmaline challenge test was negative 2 weeks later.
    explanation: >-
      Records the timing of the post-washout challenge in the one class Ic
      overdose case where it was performed and reported.
  - reference: PMID:17697824
    reference_title: Incidence of Brugada electrocardiographic pattern and outcomes of these patients after intentional tricyclic antidepressant ingestion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We evaluated 402 TCA ingestions, of which 9 (2.3%) were associated with the
      development of BEP.
    explanation: >-
      Puts a frequency on a sodium-channel-blocker-provoked pattern at
      overdose-level exposure: most people exposed do not develop it, which
      argues that individual susceptibility and not dose alone governs the
      pattern.
  - reference: PMID:30675825
    reference_title: Clinical Characteristics and Electrophysiological Mechanisms Underlying Brugada ECG in Patients With Severe Hyperkalemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The flecainide test was negative in 4 patients and positive in 1.
    explanation: >-
      In the accepted hyperkalemia category, a post-normalization challenge
      uncovered Brugada syndrome in one of five tested survivors, so the
      unmasking-versus-phenocopy ambiguity is a property of any reversible
      trigger rather than of drugs specifically.
  - reference: PMID:30675825
    reference_title: Clinical Characteristics and Electrophysiological Mechanisms Underlying Brugada ECG in Patients With Severe Hyperkalemia.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Six (40%) patients presented malignant arrhythmias and 6 died during admission.
    explanation: >-
      Contradicts a uniformly benign arrhythmic outcome for hyperkalemia-induced
      phenocopy, against the registry series quoted above. The report attributes
      the deaths to the admitting illness rather than to the ECG pattern, so the
      two cohorts differ in illness severity; see notes.
  - reference: PMID:41259431
    reference_title: Reflections on Survival Rates in Patients with Brugada PhenocopyReply.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Dado que a FB não possui o substrato patológico da SB, sua mortalidade
      reflete inerentemente a gravidade da condição subjacente.
    explanation: >-
      The classification authors' reading of why phenocopy cohorts report such
      different mortality: with no Brugada substrate present, outcome tracks the
      severity of the provoking illness. Quoted in the source's own Portuguese;
      it states that because a phenocopy lacks the pathological substrate of
      Brugada syndrome, its mortality inherently reflects the severity of the
      underlying condition.
  - reference: PMID:40052011
    reference_title: "Brugada Phenocopy due to Hyponatremia: A Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Bearing in mind that all the aforementioned transient abnormalities may
      facilitate the unmasking of BrS, after resolution of the Brugada pattern, a
      negative sodium channel blocker provocative test is obligatory to establish
      the BrP diagnosis.
    explanation: >-
      States the post-resolution negative challenge as obligatory, and gives the
      reason: any transient abnormality can unmask latent disease. Also the
      source for hyponatremia as a provoking electrolyte derangement.
  - reference: PMID:40827221
    reference_title: "Beyond the Pleura: A Case Report of Type 1 Brugada Phenocopy in the Setting of Empyema."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Right-sided empyema may represent a rare but reversible cause of Brugada
      phenocopy.
    explanation: >-
      Source for adjacent pleural-space infection as a provoking condition, an
      etiology outside the electrolyte, ischemic and mechanical groups already
      listed.
  - reference: PMID:29850266
    reference_title: Brugada Phenocopy Induced by Recreational Drug Use.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Toxicology screen was positive for cocaine, heroin, and cannabis. Initial
      electrocardiogram (EKG) showed features of a Brugada pattern in the right
      precordial leads, which resolved within one day into admission. This
      presentation is consistent with the recently recognized clinical entity
      known as Brugada phenocopy.
    explanation: >-
      Source for recreational-drug intoxication as a provoking condition. The
      authors apply the phenocopy label on reversibility alone; no post-washout
      provocative challenge is reported, which places this case with the others
      carrying the label without the classification's mandatory criterion.
  notes: >-
    No MONDO or HP term for Brugada phenocopy was found (OLS search of mondo and
    hp for "Brugada phenocopy" returned nothing; "Brugada" returned only the
    Brugada syndrome terms and ECG-pattern HP terms), so no disease_term is
    asserted.

    Whether sodium-channel-blocker toxicity can produce a phenocopy is a
    disagreement about naming, not about biology, and the post-washout
    provocative test does not settle it. The classification's authors exclude
    drug-induced patterns from the category and propose the separate label
    "acquired sodium channel dysfunction" (PMID:28958975), yet the same letter
    accepts that a propafenone overdose may produce the pattern with no genetic
    predisposition at all -- which is the substrate-free mechanism the phenocopy
    label describes. That letter replies to a specific propafenone-overdose case
    (PMID:28381391) whose post-washout ajmaline challenge was negative and whose
    family history was negative, so the case satisfies the class A criterion and
    the label was still refused. A drug-provoked pattern therefore cannot be
    classified by that test alone: PMID:29899727 is a therapeutic-dose flecainide
    case where the post-washout challenge was positive and the diagnosis became
    Brugada syndrome, while PMID:41721816 applies the phenocopy label to an
    overdose without reporting a post-washout challenge at all. The exposure
    level differs between those two cases, which is the one systematic
    difference between them, but it does not license reading a drug-provoked
    pattern as substrate-free whenever the dose was high: a Brugada pattern
    follows only 2.3% of tricyclic-antidepressant overdoses (PMID:17697824), so
    overdose-level exposure is not sufficient on its own and host susceptibility
    contributes even at that level.

    Propofol infusion syndrome is the case where this tension is sharpest.
    PMID:23094876 credits PMID:20544610 with introducing the phenocopy term for
    the Brugada-like pattern of that syndrome, then lists propofol among its
    Group 1 drugs and concludes that Group 1 drugs mostly cannot be considered
    phenocopies. Both statements are recorded here and in
    Propofol_Infusion_Syndrome rather than choosing between them; neither entry
    asserts a sodium-channel mechanism for propofol, because the cited sources
    attribute that syndrome to mitochondrial impairment and do not establish
    channel blockade as the cause of its ECG change.

    Recreational-drug intoxication is reported as its own category, separately
    from prescription antiarrhythmic toxicity: PMID:29850266 labels a
    cocaine, heroin and cannabis intoxication a phenocopy. Whether such a case
    falls under the sodium-channel-blocker exclusion above is not addressed by
    either source, and neither the case report nor the classification papers
    cited here state which of those agents block the cardiac sodium channel, so
    the entry does not place it on either side of that line. As with the class Ic
    overdose cases, no post-washout challenge is reported.

    The ambiguity is not specific to drugs. In the accepted hyperkalemia
    category, one of five post-normalization flecainide challenges was positive
    and uncovered Brugada syndrome (PMID:30675825), so consistent post-washout
    testing is warranted across every etiologic category rather than only the
    drug ones.

    Reported arrhythmic outcome differs sharply between the two hyperkalemia
    cohorts -- none in the 27-case registry series (PMID:29397883) against
    malignant arrhythmias in 40% and six in-hospital deaths in a 15-case
    critical-illness series (PMID:30675825). The deaths in the latter were
    attributed to the admitting illness (postanoxic encephalopathy, septic
    shock, malignancy, terminal hepatic disease) rather than to the ECG pattern,
    which is the reading the classification's authors give: a phenocopy carries
    no Brugada substrate, so its mortality tracks the severity of the underlying
    condition (PMID:41259431). Read a benign arrhythmic prognosis as specific to
    the cohort's illness severity, not as a property of the pattern.

    Whether reversible triggers should also be modelled as environmental[]
    entries with influences_mechanisms links is left open pending issue #10395.
discussions:
- discussion_id: q_brs_fever_query_nam_confirmation
  prompt: >-
    Can New Approach Methodologies functionally confirm SCN5A carriers surfaced by
    the fever-associated type-1 ECG case-finding query — using patient
    iPSC-cardiomyocyte and heterologous Nav1.5 temperature-challenge assays to
    show temperature-dependent sodium-current loss?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#Fever-induced accentuation of sodium-channel loss of function
  rationale: >-
    The fever→type-1-ECG mechanism is established, but a candidate surfaced by the
    EHR query still needs functional confirmation that the specific SCN5A variant
    is temperature-sensitive. A human-relevant New Approach Methodology assay — patient
    iPSC-cardiomyocytes and heterologous Nav1.5 expression subjected to a
    temperature ramp — directly measures the temperature-dependent INa loss that
    underlies fever unmasking, and is the mechanistic complement to the population
    EHR arm.
  proposed_experiments:
  - experiment_id: exp_brs_nav15_temperature_nam
    name: iPSC-cardiomyocyte and heterologous Nav1.5 temperature-challenge assay
    description: >-
      Express the candidate SCN5A variant heterologously and record INa across a
      temperature ramp (e.g. 32 to 40 degrees C); in parallel, subject
      patient-derived (and isogenic-corrected) iPSC-cardiomyocytes to the same
      temperature challenge and assess emergence of a type-1-like
      depolarization/repolarization phenotype. Temperature-dependent INa loss and
      phenotype accentuation in the variant but not the control would confirm the
      fever-sensitive substrate.
    experiment_type:
      preferred_term: iPSC-cardiomyocyte and heterologous-expression temperature-challenge assay
    model_systems:
    - name: Heterologous Nav1.5 (SCN5A) expression
      description: >-
        Candidate SCN5A variant expressed in a mammalian cell line; INa recorded
        across a temperature ramp.
      experimental_model_type: CELL_LINE
      organism:
        preferred_term: human
        term:
          id: NCBITaxon:9606
          label: Homo sapiens
    - name: Patient iPSC-derived cardiomyocytes
      description: >-
        Patient-derived and isogenic-corrected iPSC-cardiomyocytes challenged with
        a temperature ramp.
      experimental_model_type: IPSC_DERIVED_MODEL
      organism:
        preferred_term: human
        term:
          id: NCBITaxon:9606
          label: Homo sapiens
      cell_source: patient-derived and isogenic CRISPR-corrected iPSC
    perturbations:
    - name: Temperature ramp (fever challenge)
      target: pathophysiology#Fever-induced accentuation of sodium-channel loss of function
      description: Raise temperature from ~32 to ~40 degrees C, comparing variant with isogenic control.
    readouts:
    - name: Temperature-dependent sodium-current loss and arrhythmic phenotype
      target: pathophysiology#Malignant Ventricular Tachyarrhythmia
      description: >-
        INa density/gating across temperature, and emergence of type-1-like
        depolarization abnormalities / arrhythmic activity in cardiomyocytes.
    decision_criterion: >-
      Temperature-dependent INa loss and type-1-like phenotype accentuation in the
      candidate SCN5A variant but not the isogenic control.
    supporting_outcome:
    - >-
      The variant is temperature-sensitive, confirming a fever-query hit as a true
      SCN5A carrier with a fever-unmaskable substrate.
    refuting_outcome:
    - >-
      No temperature dependence, indicating the query hit is not explained by that
      variant.
- discussion_id: gap_brs_nonscn5a_gene_validity
  prompt: >-
    Do any of the individual reported non-SCN5A Brugada genes, SCN3B among them,
    have enough segregation or case-excess evidence to move out of the disputed
    tier, or are they better understood as weak-effect contributors within the
    oligogenic stratum this entry already models, or as arrhythmia genes whose
    reported Brugada association does not hold at all?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced Depolarization Reserve
  - genetic#SCN3B variants
  rationale: >-
    Twenty of the twenty-one genes curated by the reappraisal are classified as
    disputed, and the founding reports for most of them, SCN3B included, were
    sporadic cases without informative segregation data or demonstrated
    rare-variant excess. That leaves the numbered MONDO series (Brugada syndrome
    2 through 9) naming gene-specific entities whose gene-disease claims the
    field does not currently support. This entry already models the majority
    stratum as genotype-negative or oligogenic; what remains open is the status
    of these specific reported genes within it, that is, whether any individual
    one is a weak-effect contributor or simply not a Brugada gene at all. SCN3B
    is the concrete test case: its null mouse does produce reduced ventricular
    sodium current and inducible ventricular tachycardia, yet the specific human
    alleles reported for it are commoner in the population than the disease is,
    and one of them was also reported in lone atrial fibrillation. Resolving this
    determines whether this entry should ever carry gene-specific subtypes
    beyond SCN5A.
  evidence:
  - reference: PMID:29959160
    reference_title: "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "After comprehensive review by the clinical domain Expert panel, all 20 genes classified as limited evidence were reclassified as disputed with regard to any assertions of disease causality for BrS."
    explanation: >-
      Establishes that the disputed classification covers the whole non-SCN5A
      set rather than SCN3B alone, which is what makes this a stratum-level gap.
- discussion_id: mismatch_scn3b_null_mouse_atrial_phenotype
  prompt: >-
    The Scn3b-null mouse reproduces the sodium-current and ventricular
    arrhythmia phenotype, but does complete loss of beta-3 in mouse say anything
    about the heterozygous human alleles, which are commoner in the population
    than Brugada syndrome is?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - animal_models#Scn3b-null mouse (Scn3b-/-)
  - genetic#SCN3B variants
  rationale: >-
    The in vivo model and the human genetics point in opposite directions, and
    the mismatch is at the level of the allele rather than the mechanism.
    Scn3b-null mice have reduced peak sodium current in ventricular myocytes,
    shortened ventricular effective refractory periods, and inducible
    ventricular tachycardia that the authors read as resembling Scn5a
    heterozygous hearts, so loss of beta-3 plainly can produce a
    sodium-channel-dependent ventricular arrhythmic substrate. But the model is
    a homozygous null, while every reported human variant is heterozygous, and
    two of them occur in the general population at roughly the prevalence of
    Brugada syndrome itself. So a strong model phenotype coexists with human
    alleles that cannot carry the disease at the frequency observed. Either the
    reported missense alleles do not approach the functional severity of a null,
    or beta-3 loss contributes only as a modifier on other substrate. Which of
    those holds determines whether the disputed classification is a statement
    about SCN3B or only about the specific alleles so far reported, and a
    heterozygous knock-in of the human alleles is the experiment that would
    separate them. Note that this discussion_id predates the question it now
    asks: it was first written around an apparent atrial-versus-ventricular
    mismatch that the Hakim 2008 ventricular data disproved. The id is retained
    as a stable key and should not be read as the claim.
  evidence:
  - reference: PMID:19351516
    reference_title: Scn3b knockout mice exhibit abnormal ventricular electrophysiological properties.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Together, these findings associate the lack of the Scn3b gene with arrhythmic tendencies in intact perfused hearts and electrophysiological features similar to those in Scn5a(+/-) hearts."
    explanation: >-
      Establishes the strong model-side phenotype that makes the contrast with
      the human allele frequencies a genuine mismatch rather than a simple
      absence of model support.
  - reference: PMID:29959160
    reference_title: "Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Two curated genes in this study were originally implicated on the basis of variants suggested to be rare in the original studies, only to be subsequently noted to have heterozygosity frequency in public databases greater than or equal to the prevalence of BrS (KCNJ8 p.Ser422Leu, 1/250; SCN3B p.Leu10Pro, p.Val110Ile, both 1/2500)."
    explanation: >-
      The human-side half of the mismatch: the specific reported alleles are too
      common to cause the disease, whatever the null mouse shows.
notes: >-
  This entry is curated as the inherited arrhythmia root for Brugada syndrome
  rather than as a long-QT-like subtype series. It absorbs the Brugada root and
  related gene-specific rows by representing SCN5A-related Brugada syndrome as
  the only explicit monogenic subtype while leaving the majority genotype-negative
  or oligogenic stratum explicit. In the local 2026-03-28 G2P triage snapshot,
  disputed or unresolved non-SCN5A Brugada links exist for ANK2, CACNA2D1,
  CACNB2, GPD1L, HCN4, KCND3, KCNE3, KCNH2, KCNJ8, PKP2, RANGRF, SCN10A, SCN2B,
  SCN3B, SLMAP, and TRPM4; CACNA1C and SCN1B also appear in non-root or
  embedded contexts. Those associations are intentionally handled here as
  disease-level heterogeneity rather than promoted to standalone validated
  monogenic disease roots. The gene-specific MONDO child terms in that numbered
  series are to be bound here as skos:narrowMatch mappings rather than as
  has_subtypes rows, so ontology coverage is recorded without placing a disputed
  gene at the same structural weight as the definitive SCN5A form.
  MONDO:0013146 (Brugada syndrome 7, SCN3B) was the first bound this way, and the
  series is now complete: Brugada syndrome 2 (GPD1L), 3 (CACNA1C), 4 (CACNB2),
  5 (SCN1B), 6 (KCNE3), 8 (HCN4) and 9 (KCND3) are all bound as skos:narrowMatch
  mappings, and each of those genes now has a genetic-section record with
  relationship_type DISPUTED carrying the specific reappraisal finding against it.

  Two things checked in the same pass are recorded because they explain why a
  gene-keyed comparison over this series misreports it. Brugada syndrome 1
  (MONDO:0011001) and Brugada syndrome 3 (MONDO:0012742) carry no direct
  RO:0004003 gene edge in MONDO at all; each inherits its gene from a second,
  gene-named parent — MONDO:1010181 SCN5A-related cardiac rhythm disorder and
  MONDO:0700321 CACNA1C-related disorder respectively — so a comparison keyed on
  gene edges omits the one Brugada gene ClinGen calls definitive. And ClinGen has
  moved past the 2018 reappraisal for three of these genes: SCN3B is now refuted
  rather than disputed, and current SOP11 assertions exist for CACNA1C, CACNB2
  and KCNE3.

  SCN3B remains the only disputed gene wired onto a pathophysiology node. The
  eight other disputed records are deliberately not wired: placing a disputed
  gene on the reduced-depolarization-reserve node would assert in this disease
  exactly the causal role ClinGen declined to accept. SCN3B is the exception this
  entry already argued for on the strength of its Scn3b-null mouse phenotype, and
  that argument stays inside its own record rather than being generalised to the
  rest.
datasets:
- accession: geo:GSE264359
  title: A rare non-coding enhancer variant in SCN5A contributes to the high prevalence of Brugada syndrome in Thailand
  description: 'Brugada syndrome (BrS) is a cardiac arrhythmia disorder that causes sudden death in young adults. Rare genetic variants in the SCN5A gene, encoding the Nav1.5 sodium channel, and common non-coding variants at this locus, are robustly associated with the condition. BrS is particularly prevalent in Southeast Asia but the underlying ancestry-specific factors remain largely unknown. Methods: Genome sequencing of BrS probands and population-matched controls from Thailand was performed to identify rare non-coding variants at the SCN5A-SCN10A locus that were enriched in BrS cases.'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 8
  publication: PMID:39391988
  notes: Identified by GEO DataSets index search for Brugada syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE278421
  title: N-Palmitoylglycine activates transient receptor potential channel 5 and increases the risk of Brugada syndrome
  description: Brugada syndrome (BrS) is an arrhythmic disorder associated with an increased risk of sudden cardiac death; however, current treatment options are limited due to their side effects and variable efficacy. In this study, we employed Mendelian randomization analysis utilizing proteomic, transcriptomic, and metabolomic data to identify potential therapeutic targets for BrS. Our findings indicate that N-palmitoylglycine (PalGly) is linked to an increased risk of BrS and interacts with BrS-associated proteins, demonstrating moderate binding affinities for proteins such as DCC, CR1, CTSB, NAAA, DEFB1, EPHA1, IGF1/IGFBP3/ALS, and LTA.
  organism:
    preferred_term: rat
    term:
      id: NCBITaxon:10116
      label: Rattus norvegicus
  data_type: BULK_RNA_SEQ
  sample_count: 10
  publication: PMID:41315851
  notes: Identified by GEO DataSets index search for Brugada syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE46348
  title: Illumina SNP array data for Brugdata syndrome patients in Taiwan
  description: Background Brugada syndrome (BrS) is a rare inherited disease causing sudden cardiac death (SCD). Copy number variants (CNVs) can contribute to disease susceptibility, but their role in Brugada syndrome (BrS) is unknown. We aimed to identify a CNV associated with BrS and elucidated its clinical implications. Methods We enrolled 335 unrelated BrS patients from 2000 to 2018 in the Taiwanese population. Microarray and exome sequencing were used for discovery phase whereas Sanger sequencing was used for the validation phase. HEK cells and zebrafish were used to characterize the function of the CNV variant.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: GWAS
  sample_count: 16
  publication: PMID:32645615
  notes: Identified by GEO DataSets index search for Brugada syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001003059
  title: Brugada Syndrome-associated Genetic Loci are associated with J-point Elevation and an Increased Risk of Cardiac Arrest
  description: 'Introduction: A previous genome-wide association study found three genetic loci, rs9388451, rs10428132, and rs11708996, toincrease the risk of Brugada Syndrome (BrS). Since the effect of these loci in the general population is unknown, we aimed toinvestigate the effect on electrocardiogram (ECG) parameters and outcomes in the general population.Material and Methods: A cohort of 6,161 individuals (median age 45 [interquartile range (IQR) 40-50] years, 49% males), withavailable digital ECGs, was genotyped and subsequently followed for a median period of 13 [IQR 12.6-13.4] years. Data on outcomeswere collected from Danish administrative healthcare registries.'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Brugada syndrome"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001004927
  title: Short and long-read sequencing of Brugada syndrome samples
  description: Genome-wide association studies (GWAS) are instrumental in identifying loci with an impact on human traits and disease. Typically, however, most GWAS information is considered redundant as it is based on neighboring single-nucleotide variants (SNVs) in strong linkage disequilibrium (LD). In this context, besides the most significant hit (lead SNV) in every trait- or disease-associated locus, the rest of GWAS hits are often marginally reported, examined, or exploited.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Brugada syndrome"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001005848
  title: Searching for genetic modulators of the phenotypic heterogeneity in Brugada Syndrome
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: WES
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Brugada syndrome"); description-level mentions were not accepted. EGA study_type: Exome Sequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
references:
- reference: PMID:20301690
  title: "Brugada Syndrome."
  tags:
  - GeneReviews
  findings: []

📚

References & Deep Research

References

1

PMID:20301690

Brugada Syndrome.

No top-level findings curated for this source.

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Deep research on the Brugada phenocopy differential; drug-trigger question resolved as terminological · 2026-09-26T19:07:11Z · View source

Ran the two deep-research passes issue #12917 recorded as outstanding after PR #12924: a general report against templates/disease_pathophysiology_research.md, and a phenocopy-focused report against a new templates/disease_phenocopy_research.md, which asks for the published classification, the etiologic categories, the contested drug category with a per-case table of post-washout challenge results, dose dependence, prognosis and a verdict. Both reports requested falcon and fell back to claude_code; the reports carry fell_back, requested_provider and provider_attempts, and align_research_provider renamed both to the provider that wrote them. The earlier session recorded the falcon failure as a network proxy blocking Edison authentication. That is not why the fallback failed here: the nested Claude Code run returns exit code 1 with empty stderr because the request is refused by a model-level safety classifier (stop_reason refusal, category bio), which deep-research-client surfaces only as "<no stderr>". Setting ANTHROPIC_MODEL for the client process steers the nested CLI past it, which --param cannot do because it reaches the primary provider and never the fallback. Both reports were produced with the provider's default working directory, which is the repository root, so CLAUDE.md was loaded into the nested agent's context. Each report contains a sentence about this repository as a result. In the general report that sentence claims a differential-diagnosis addition was just made to this entry, which the nested agent could not have read (its tool allowlist was WebSearch and WebFetch only), so it is an unsupported claim about repository state. The reports are committed as produced rather than edited, since editing provider output would falsify its provenance. Future runs of this provider should set working_dir outside the repository. Curation the research changed. The contested question, whether sodium-channel-blocker toxicity can produce a phenocopy, is a disagreement about naming rather than about biology, and the previous notes were wrong to say the post-washout provocative test reconciles the two positions. The classification's authors exclude drug-induced patterns and propose the separate label "acquired sodium channel dysfunction" (PMID:28958975), while the same letter accepts that a propafenone overdose may produce the pattern with no genetic predisposition. That letter is a reply to a specific propafenone-overdose case (PMID:28381391) whose post-washout ajmaline challenge and family history were both negative, so the case meets the class A criterion and the label was refused anyway. Added the tricyclic series (PMID:17697824), where the pattern follows 2.3% of 402 overdoses: that rate shows overdose-level exposure is not sufficient on its own, so host susceptibility contributes even at that level. An earlier draft of the notes read the same figure as making dose the discriminator, which contradicted the evidence item's own explanation and was corrected in review. Also recorded that the ambiguity is not specific to drugs: in the accepted hyperkalemia category one of five post-normalization flecainide challenges was positive and uncovered Brugada syndrome (PMID:30675825). The same cohort reports malignant arrhythmias in 40% and six in-hospital deaths, against none in the 27-case registry series already cited (PMID:29397883), so that second cohort is recorded as a REFUTE item and the divergence is explained in notes by the reading that a phenocopy carries no Brugada substrate and its mortality tracks the provoking illness (PMID:41259431, quoted in the source's own Portuguese). Added hyponatremia (PMID:40052011) and pleural empyema (PMID:40827221) as provoking conditions, and named hypokalemia, pectus excavatum, acute pericarditis, septic shock and acute coronary occlusion in the description. Also took the three non-blocking suggestions from the approving review of PR #12924, which that PR's author held back so as not to drop its approval: reworded the propafenone distinguishing feature to say the case was reported as a phenocopy, made the case-report reference singular, and bound the type 2 pattern to HP:6000985 Saddle-back type ST segment elevation as a second phenotype. Two report-level flags left as they are, because a report is a lead rather than content. The focused report's own reference validation rejects one quote it attributed to PMID:28381391; that quote is a paraphrase, and the entry cites the paper's actual conclusion sentence instead. The general report has two quotes rejected against PMID:42123485, neither of which is used here. The focused report also flags as PLAUSIBLE-only a genetic-yield figure and a HRS/EHRA/APHRS consensus statement it could not quote directly; neither is cited in the entry. Review round 2 added recreational-drug intoxication as a provoking condition, citing PMID:29850266, whose cache this branch already carried from the research runs without citing it. That case's authors apply the phenocopy label to a cocaine, heroin and cannabis intoxication on reversibility alone, with no post-washout challenge reported. The notes record that neither that report nor the classification papers cited here state which of those agents block the cardiac sodium channel, so the entry does not place the case on either side of the sodium-channel-blocker exclusion rather than asserting a pharmacological claim no cited source here carries. Nothing was added to environmental[] or influences_mechanisms, still pending issue #10395. Validation on the changed entry: just validate (117/117 snippets, 121 titles), validate-terms, count-verified-snippets, check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, and the batched validate-disorders all pass. Whole-KB gates run clean: check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-reference-titles, check-coarse-phenotypes, check-enum-values and check-case-collisions. No baseline file was updated.

Add Brugada phenocopy differential diagnosis · 2026-09-26T17:32:05Z · View source

Added a differential_diagnoses entry for Brugada phenocopy (issue #12917): definition, reported provoking conditions, a shared HP:6000984 phenotype, five distinguishing features, and ten evidence items from nine PMIDs. No MONDO or HP term for Brugada phenocopy exists (OLS search of mondo and hp), so no disease_term is set. The evidence surfaced a disagreement the issue did not anticipate. The phenocopy classification authors (PMID:25201124) state that sodium channel blockers do not cause a phenocopy but unmask latent Brugada syndrome, while PMID:41721816 calls a propafenone overdose a drug-induced phenocopy. PMID:29899727, which the issue listed as a flecainide-induced Brugada pattern, turned out to be a case of unmasked Brugada syndrome: ajmaline challenge after washout was positive. It is therefore cited as the counter-example, and the notes explain how a post-washout provocative test decides between the two readings. Two PMIDs from the issue were not used: PMID:23317529 has no retrievable abstract or full text, and the PMID:30177318 abstract does not mention the Brugada pattern. environmental[] influences_mechanisms links were deliberately not added, pending #10395. Deep research: falcon was requested but failed twice (once plain, once with --fallback) because the environment proxy returned 403 on Edison authentication, and the fallback could not engage before the failure. No report was produced, and the entry was written from the cached primary sources the issue had already gathered. Validation: just validate, validate-terms, count-verified-snippets (107/107), check-duplicate-keys, check-entity-refs, check-causal-targets, check-enum-values, check-snippet-length, check-title-snippets, check-snippet-grading, and validate-disorders all passed.

Lump Brugada syndrome 7 (MONDO:0013146, SCN3B) onto the Brugada root entry · 2026-09-03T06:33:16Z · View source

Curation target was Brugada syndrome 7 (MONDO:0013146). Outcome is a lump onto the existing Brugada_Syndrome.yaml root rather than a standalone entry, per the ruling in issue #8921 (closed not_planned by @sierra-moxon: the priority dashboard marks the term LUMP_INTO_PARENT and the claim-disease skill excludes such rows). Identity anchored on OAK, not on any research report: runoak confirmed MONDO:0013146 is_a MONDO:0015263, intersection_of RO:0004003 HGNC:20665 (SCN3B), OMIM:613120; hgnc:20665 confirmed as SCN3B. Three changes: (1) mappings.mondo_mappings gains MONDO:0013146 as skos:narrowMatch, following the Alagille_syndrome narrowMatch precedent, with a justification stating why a disputed gene is not given has_subtypes weight beside the definitive SCN5A form; (2) a new genetic entry 'SCN3B variants' with relationship_type DISPUTED and seven evidence items, which moves the SCN3B claim out of prose in notes and into a machine-readable record; (3) a KNOWLEDGE_GAP discussion (gap_brs_nonscn5a_gene_validity) attached to pathophysiology#Reduced Depolarization Reserve and genetic#SCN3B variants, asking whether the non-SCN5A stratum is oligogenic or simply not Brugada genes. The stub stubs/Brugada_Syndrome_7.yaml is deleted; the entry_type decision is SUBTYPE in substance, and the reasoning is recorded durably in the parent entry's notes and mapping_justification rather than in the deleted stub. Deep research: falcon was requested and returned HTTP 403 on authentication, so the run was re-issued with --fallback and openscientist produced research/Brugada_Syndrome_7-deep-research-openscientist.md, which records fell_back, requested_provider and provider_attempts in its frontmatter; no provider was substituted by hand. That report's reference validation was 31/31 verified (confabulation_rate 0.0) but its term validation was poor, 9 of 15 labels mismatched including MONDO:0013481 offered as 'brugada syndrome 7' when it is chromosome 13q14 deletion syndrome, plus NCIT:C50032 'Limiter Device' offered as ICD and NCIT:C371 'Chromomycin Antineoplastic Antibiotic' offered as isoproterenol; no CURIE was taken from the report. The report also omitted PMID:20031595, the seminal SCN3B paper, which came from the issue thread instead, and it reported the ClinGen tier as 'limited', which is the curator-team tier superseded by the expert panel's disputed reclassification in the primary. What the report did contribute was PMID:23257389, the Japanese V110I cohort giving 3 of 178 SCN5A-negative patients, which corrected an initial draft that described the association as resting on a single proband. Validation: just validate (62/62 snippets verified), just validate-disorders (schema, terms and references, all passed), check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-enum-values, check-snippet-grading, check-title-snippets, check-snippet-length, check-folded-hyphens and check-stubs all clean with no new baseline rows. Pre-PR red-team review (dismech-pr-review skill, fresh-context subagent) found and this commit fixed: (1) the features block asserted that a 1 in 2500 population frequency exceeds a 1 in 2000 disease prevalence, which is arithmetically backwards, and drew the unsupported conclusion 'incompatible with a causal role' - both replaced by the reappraisal's own framing, at or above the population prevalence and incompatible with a highly penetrant monogenic causal role; (2) the entry claimed two SCN3B variants carry the association while PMID:39761910, already in this PR's own reference cache, reports a third (T138del) with preserved surface expression, which also falsified the generalisation that all act by mistrafficking - the common mechanism is now stated as reduced sodium current and that paper is cited; (3) directness INDIRECT on the human proband observation was a strength judgement rather than a directness one and was inverted relative to the in-vitro items, corrected to DIRECT with the two-directional explanation trimmed; (4) evidence_source on the two expert-panel verdict snippets changed from HUMAN_CLINICAL to OTHER, since a consensus verdict is not primary clinical data; (5) the notes block stated the narrowMatch policy as executed across the series when only MONDO:0013146 is bound, reworded as prospective and naming the seven unmapped terms; (6) the discussion prompt narrowed so it no longer reopens the oligogenic-architecture question the has_subtypes entry already answers; (7) PMID:21051419 added, reporting L10P, the original Brugada allele, in a lone atrial fibrillation cohort, which is direct support for the disputed call; (8) 'twenty-one genes reported' corrected to 'curated' (the reappraisal identified 23 and curated 21) and 'neither report provided segregation data' to 'no report provided informative segregation data', since PMID:20031595 does report one uninformative unaffected-brother data point. Separately, an independent exact-substring check found the PMID:39761910 snippet had been transcribed with 'beta3' where the source has the Greek character; the reference validator normalises that and passed it 64/64, so the snippet was corrected to the source characters rather than left relying on normalisation. All 42 PMID snippets in the file were then re-checked and match. Left for follow-up: the entry still has no top-level references block and no GeneReviews baseline, a pre-existing gap that predates this session. A second round, after the ai4c-reviewer review on PR #10676, closed the one blocking finding: the Scn3b-null mouse phenotype had been asserted in the genetic features block and in the knowledge-gap rationale with no evidence item at all, although PMID:19796257 was already in the reference cache. That is now cited, and the model is curated as an animal_models entry with a modeled_mechanisms link. Two departures from the reviewer's suggested fix, both because the source does not support it: the relationship is PARTIALLY_RECAPITULATES rather than FAILS_TO_RECAPITULATE, and the evidence item is SUPPORT/INDIRECT rather than REFUTE, because PMID:19796257 describes its atrial findings as complementing ventricular changes reported on an earlier occasion, so it does not establish that a ventricular phenotype is absent. The curated prose that said the mouse shows conduction disease 'rather than' the right-ventricular substrate carried that same overclaim and was corrected in both places. A HUMAN_MODEL_MISMATCH discussion was added for the translational question and kept separate from the gene-validity KNOWLEDGE_GAP, which asks a different question. Also from that review: the literature-census snippet was regraded from HUMAN_CLINICAL to OTHER for consistency with the two expert-panel items, the PMID:21051419 reference_title restored to the cache-exact Greek beta, and three stray blank lines removed. A third round corrected a factual error introduced by the second. While defending the choice of PARTIALLY_RECAPITULATES over the reviewer's suggested FAILS_TO_RECAPITULATE, a PubMed search for the ventricular study that PMID:19796257 refers to as 'an earlier occasion' found PMID:19351516, Hakim et al. 2008, which reports that Scn3b-null mice have reduced peak sodium current in ventricular myocytes, shortened ventricular effective refractory periods, and inducible monomorphic or polymorphic ventricular tachycardia, with electrophysiological features the authors describe as similar to Scn5a heterozygous hearts. The curated prose asserting that the null phenotype is atrial and conduction dominated rather than right-ventricular was therefore wrong, not merely unsupported, and FAILS_TO_RECAPITULATE would have been badly wrong. Both prose sites were rewritten, PMID:19351516 was cached and cited, a second modeled_mechanisms link to Malignant Ventricular Tachyarrhythmia was added, fidelity on the depolarization-reserve link was raised from LOW to MODERATE now that reduced ventricular sodium current is directly measured, and the limitations were reduced to the two that survive: homozygous null against heterozygous human alleles, and murine versus human ventricular repolarization. The HUMAN_MODEL_MISMATCH discussion was rewritten around the mismatch that actually exists, which is allele-level rather than compartment-level: a strong null-mouse phenotype coexisting with human alleles that occur at roughly the prevalence of the disease. check-snippet-grading then caught the population-frequency snippet graded OTHER in the new discussion and HUMAN_CLINICAL in the genetic block; the HUMAN_CLINICAL grading was kept in both. 75/75 snippets verified. A fourth round closed a leftover from the third. The readout interpretation on 'Atrial arrhythmia inducibility on burst pacing' still read 'The arrhythmia this model actually produces is atrial rather than ventricular, which is the substance of the translational mismatch'. Both clauses were false once PMID:19351516 was curated forty lines below in the same file: the model does produce inducible ventricular tachycardia, and the mismatch had been reframed in that same commit from chamber to allele. This was the third occurrence of one 'X rather than Y' absence-implication; the other two were corrected and this one was missed, and nothing gates a free-text interpretation field. A regex sweep over every string in the entry was then run to check for further instances: the remaining 'rather than' occurrences are contrastive curation statements or accurate, and none assert an absent phenotype. Two non-blocking suggestions were also taken: the depolarization-reserve link description now states the directly measured reduction in ventricular peak sodium current rather than only conduction slowing, and the mismatch discussion rationale records that its discussion_id predates the reframing so the id is not read as the claim; the id itself was kept as a stable key.

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Brugada syndrome. Core disease mechanisms, molecular and cellular pathways...

Asta Scientific Corpus Retrieval 20 citations 2026-04-14T00:42:58.164436

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Brugada syndrome. Core disease mechanisms, molecular and cellular pathways...

This report is retrieval-only and is generated directly from Asta results.

Papers retrieved: 20
Snippets retrieved: 20

Relevant Papers

[1] Single Cell Transcriptomics Trajectory and Molecular Convergence of Clinically Relevant Mutations in Brugada Syndrome.

Authors: Richa Tambi, Reem Abdel Hameid, Asma R. Bankapur, Nasna Nassir, G. Begum et al.
Year: 2021
Venue: American journal of physiology. Heart and circulatory physiology
URL: https://www.semanticscholar.org/paper/4458fe1e74cb382da1dc5c596ed05dee7dbae385
DOI: 10.1152/ajpheart.00061.2021
PMID: 33797273
Citations: 6
Summary: It is suggested that genomic and proteomic hotspots in BrS converge into ion transport pathway and cardiomyocyte as a major BrS associated cell type that provides insight into the complex genetic etiology of BrS.
Evidence snippets:
Snippet 1 (score: 0.487) > Brugada syndrome (BrS) is a rare, inherited arrhythmia with high risk of sudden cardiac death. To evaluate the molecular convergence of clinically relevant mutations and to identify developmental cardiac cell types that are associated with BrS etiology, we collected 733 mutations represented by 16 sodium, calcium, potassium channels, regulatory and structural genes related to BrS. Among the clinically relevant mutations, 266 are unique singletons and 88 mutations are recurrent. We observed an over representation of clinically relevant mutations (~80%) in SCN5A gene, and also identified several candidate genes, including GPD1L, TRPM4 and SCN10A. Furthermore, protein domain enrichment analysis revealed that a large proportion of the mutations impacted ion-transport domains in multiple genes, including SCN5A, TRPM4 and SCN10A. A comparative protein domain analysis of SCN5A further established a significant (p=0.04) enrichment of clinically relevant mutations within ion-transport domain, including a significant (p=0.02) mutation hotspot within 1321-1380 residue. The enrichment of clinically relevant mutations within SCN5A ion transport domain is stronger (p=0.00003) among early onset of BrS. Our spatiotemporal cellular heart developmental (prenatal to adult) trajectory analysis applying single cell transcriptome identified the most frequently BrS mutated genes (SCN5A and GPD1L) are significantly upregulated in the prenatal cardiomyocytes. A more restrictive cellular expression trajectory is prominent in the adult heart ventricular cardiomyocytes compared to prenatal. Our study suggests that genomic and proteomic hotspots in BrS converge into ion transport pathway and cardiomyocyte as a major BrS associated cell type that provides insight into the complex genetic etiology of BrS.

[2] Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patient

Authors: E. Selga, F. Sendfeld, R. Martínez-Moreno, Claire N. Medine, O. Tura-Ceide et al.
Year: 2018
Venue: Journal of Molecular and Cellular Cardiology
URL: https://www.semanticscholar.org/paper/58904fb4a8370cf03af046e5fa2828965e5dbf62
DOI: 10.1016/j.yjmcc.2017.10.002
PMID: 29024690
PMCID: 5807028
Citations: 52
Influential citations: 4
Summary: Cardiomyocytes derived from iPS cells from a Brugada syndrome patient with a mutation in SCN5A recapitulate the loss of function of sodium channel current associated with this syndrome; including pro-arrhythmic changes in channel function not detected using conventional heterologous expression systems.
Evidence snippets:
Snippet 1 (score: 0.463) > Brugada syndrome is an autosomal dominant hereditary condition that is responsible for 20% of sudden cardiac deaths of patients with structurally normal hearts [1]. It is characterized by an abnormal electrocardiogram with ST-segment elevation in the right precordial leads V 1 to V 3 and right bundle-branch block frequently leading to ventricular fibrillation [2]. Patients often present symptoms of ventricular tachycardia, bradycardia, and atrial ventricular node conduction disorder, and more males than females are diagnosed with Brugada syndrome. To date, the implantation of a cardioverter defibrillator is the only proven effective treatment of the disease [3,4]. Whilst Brugada syndrome has been associated with mutations in 23 genes [5], the majority of these disease-related mutations have been found in SCN5A [6]. This gene encodes the alpha-subunit of the cardiac sodium channel (Na v 1.5) which is responsible for the sodium inward current (I Na ). Heterologous expression of recombinant Na v 1.5 channels in conventional cellular systems has provided invaluable insight into the molecular and electrophysiological basis of Brugada syndrome. Still, the main limitation of this approach is that the cells typically used (i.e., HEK293 cells, Xenopus oocytes) deviate considerably from human cardiomyocytes in many relevant aspects. These cells do not reflect the modulatory effects of accessory channel subunits or the influence of potential compensatory pathways, both of which could take place in native cardiomyocytes. Thus, studies of mutant channels using such expression systems might be missing important characteristics of native cardiomyocytes relevant to pathophysiology. > The differentiation of induced pluripotent stem (iPS) cells from patients with cardiac diseases into cardiomyocytes (iPS-CM) provides a cell model highly homologous to native human cardiomyocytes. The use of these surrogate cells allows investigators to study mutant ion channels in their native patient-specific cell environment. This includes all their regulatory proteins, and importantly, a physiologically controlled level of protein expression. To date, several cardiac channelopathies including long QT syndrome

[3] Sudden cardiac death and inherited channelopathy: the basic electrophysiology of the myocyte and myocardium in ion channel disease

Authors: C. A. Martin, Gareth D. K. Matthews, C. Huang
Year: 2012
Venue: Heart
URL: https://www.semanticscholar.org/paper/29976470123eed75b8f529e1e4485294a96481a9
DOI: 10.1136/heartjnl-2011-300953
PMID: 22422742
PMCID: 3308472
Citations: 73
Influential citations: 5
Summary: Basic research using molecular techniques, as well as animal models, has proved extremely useful in improving knowledge of inherited arrhythmogenic syndromes and provides novel markers for risk assessment and a basis for new strategies of treatment.
Evidence snippets:
Snippet 1 (score: 0.460) > Ion channels are pore-forming proteins that provide pathways for the controlled trans-membrane movement of ions. This is critical for a range of physiological processes including action potential (AP) generation and propagation, resulting in the release of intracellular Ca 2+ stores triggering mechanical activity. Abnormalities in cardiac ion channel function or in their associated regulatory proteins may lead to arrhythmias and sudden cardiac death (SCD). SCD poses a major medical challenge and significant public health burden, accounting for over 300 000 deaths per year in the USA, 1 and up to 70 000 deaths per year in the UK, 2 with survival rates of only 2%. In the majority of cases, the arrhythmias are a manifestation of underlying ischaemic heart disease; however, autopsy fails to reveal a cause in up to 40% of SCD patients. 3 Despite the high prevalence and large impact on society of cardiac arrhythmias, our understanding of the cellular and molecular mechanisms governing the initiation, maintenance and propagation of arrhythmias remains limited. Consequently, current risk stratification of patients and families with these conditions is inadequate and the mainstay of treatment is often restricted to implantable cardioverter defibrillator implantation. Although new techniques are being developed to investigate the mechanisms that predispose to SCD, invasive studies in humans are limited. Therefore, basic research using molecular techniques as well as animal models is essential in improving our understanding of the mechanisms of arrhythmogenesis at the cellular level. This review forms the third paper in a series of inherited channelopathy reviews published in this journal, with the earlier papers discussing the impact of pathophysiology 4 and the role of the Sudden Adult Death Syndrome clinic 5a in the management of ion channel disease. The current review will focus on the role of basic science in investigating primary electrical diseases of the heart as a paradigm for cardiac arrhythmias, concentrating on Brugada syndrome (BrS), long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT).

[4] Electrophysiological Mechanisms of Brugada Syndrome: Insights from Pre-clinical and Clinical Studies

Authors: G. Tse, Tong Liu, K. H. C. Li, V. Laxton, Y. W. Chan et al.
Year: 2016
Venue: Frontiers in Physiology
URL: https://www.semanticscholar.org/paper/8d4acfb8df7ee01acd6c2d82a8f73ab8ee2a55f9
DOI: 10.3389/fphys.2016.00467
PMID: 27803673
PMCID: 5067537
Citations: 54
Influential citations: 3
Summary: Evidence from computational modeling, pre-clinical, and clinical studies illustrates that molecular abnormalities found in BrS lead to alterations in excitation wavelength (λ), which ultimately elevates arrhythmic risk.
Evidence snippets:
Snippet 1 (score: 0.457) > Brugada syndrome (BrS), is a primary electrical disorder predisposing affected individuals to sudden cardiac death via the development of ventricular tachycardia and fibrillation (VT/VF). Originally, BrS was linked to mutations in the SCN5A, which encodes for the cardiac Na+ channel. To date, variants in 19 genes have been implicated in this condition, with 11, 5, 3, and 1 genes affecting the Na+, K+, Ca2+, and funny currents, respectively. Diagnosis of BrS is based on ECG criteria of coved- or saddle-shaped ST segment elevation and/or T-wave inversion with or without drug challenge. Three hypotheses based on abnormal depolarization, abnormal repolarization, and current-load-mismatch have been put forward to explain the electrophysiological mechanisms responsible for BrS. Evidence from computational modeling, pre-clinical, and clinical studies illustrates that molecular abnormalities found in BrS lead to alterations in excitation wavelength (λ), which ultimately elevates arrhythmic risk. A major challenge for clinicians in managing this condition is the difficulty in predicting the subset of patients who will suffer from life-threatening VT/VF. Several repolarization risk markers have been used thus far, but these neglect the contributions of conduction abnormalities in the form of slowing and dispersion. Indices incorporating both repolarization and conduction and based on the concept of λ have recently been proposed. These may have better predictive values than the existing markers.

[5] Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

Authors: T. Nakajima, S. Tamura, M. Kurabayashi, Y. Kaneko
Year: 2021
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/3d299f57f344d42eff9d3565d1581dae7fb87a54
DOI: 10.3390/ijms22083930
PMID: 33920294
PMCID: 8069124
Citations: 6
Influential citations: 1
Summary: Since the epileptic phenotype appears to manifest prior to cardiac events in this mutation carrier, identifying KCND3 mutations in patients with epilepsy and providing optimal therapy will help prevent sudden unexpected death in epilepsy.
Evidence snippets:
Snippet 1 (score: 0.457) > Recent advances in molecular genetics have identified many causal genes for inherited arrhythmia syndromes (IASs) such as long QT syndrome (LQTS) [1], short QT syndrome (SQTS) [2], Brugada syndrome (BrS) [3,4] and early repolarization (ER) syndrome (ERS) [3,5]. Most causal genes for IASs encode cardiac ion channels or their related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterologous expression systems and experimental animal models, have revealed the pathophysiology of IASs and enabled the establishment of causal gene-specific precision medicine [6][7][8]. Furthermore, analyses of patient-specific and/or genome-edited induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have provided further insights into the pathophysiology of IASs and novel promising therapeutic strategies for IASs, although there are still some limitations of using iPSC-CMs, such as immature structure and function and mixed population of atrial, ventricular, and nodal cells, as a standard technology [9]. > The altered function of causal genes that encode cardiac ion channels is caused by multiple mechanisms, including trafficking defects, producing non-functional channels, altered channel gating properties, and a combination thereof. These altered functions of mutant channels underly the clinical phenotypes of IASs [10][11][12]. Particularly, unique electrophysiological properties of mutant channels have been shown to be associated with the atypical clinical phenotypes of IASs [10,13]. Furthermore, the elucidation of the mechanisms underlying the atypical clinical phenotypes of IASs has raised the possibility of mutation-specific precision medicine. > We herein review the current knowledge of genotype-phenotype relationships, underlying molecular and cellular mechanisms, and established pharmacological therapies of IASs, including LQTS, SQTS, and J wave syndrome (BrS and ERS).

[6] J wave syndrome: Benign or malignant?

Authors: Alborz Sherafati, M. Eslami, Reza Mollazadeh
Year: 2021
Venue: ARYA Atherosclerosis
URL: https://www.semanticscholar.org/paper/c6ffd16e004d12c90e5acac0f7df05d8cb202b71
DOI: 10.22122/arya.v17i0.2259
PMID: 35685231
PMCID: 9137236
Citations: 1
Summary: This paper describes 2 patients with early repolarization and Brugada syndrome, and discusses their definition, epidemiology, genetics, cellular mechanism, diagnosis, risk stratification, and finally, therapeutic challenges and options one by one in detail.
Evidence snippets:
Snippet 1 (score: 0.453) > J wave syndrome is an electrical disease of the heart due to pathologic early repolarization. It encompasses a clinical spectrum from aborted sudden cardiac death due to ventricular arrhythmia (VA) usually in young affected patients to self-terminating ventricular ectopies, and finally, asymptomatic relatives of probands detected during electrocardiography acquisition (early repolarization pattern). This syndrome consists of 2 phenotypes, early repolarization and Brugada syndrome. Herein, we first describe 2 patients with early repolarization and Brugada syndrome, then, discuss their definition, epidemiology, genetics, cellular mechanism, diagnosis, risk stratification, and finally, therapeutic challenges and options one by one in detail.

[7] The Mechanism of Ajmaline and Thus Brugada Syndrome: Not Only the Sodium Channel!

Authors: M. Monasky, E. Micaglio, S. D’Imperio, C. Pappone
Year: 2021
Venue: Frontiers in Cardiovascular Medicine
URL: https://www.semanticscholar.org/paper/17af37987335d9ae6f2219b4e0a922fa6f82428c
DOI: 10.3389/fcvm.2021.782596
PMID: 35004896
PMCID: 8733296
Citations: 13
Summary: Clinical studies have implicated several candidate genes in BrS, encoding not only for sodium, potassium, and calcium channel proteins, but also for signaling- related, scaffolding-related, sarcomeric, and mitochondrial proteins, which could prove absolutely relevant in the mechanism of BrS.
Evidence snippets:
Snippet 1 (score: 0.452) > Ajmaline is an anti-arrhythmic drug that is used to unmask the type-1 Brugada syndrome (BrS) electrocardiogram pattern to diagnose the syndrome. Thus, the disease is defined at its core as a particular response to this or other drugs. Ajmaline is usually described as a sodium-channel blocker, and most research into the mechanism of BrS has centered around this idea that the sodium channel is somehow impaired in BrS, and thus the genetics research has placed much emphasis on sodium channel gene mutations, especially the gene SCN5A, to the point that it has even been suggested that only the SCN5A gene should be screened in BrS patients. However, pathogenic rare variants in SCN5A are identified in only 20–30% of cases, and recent data indicates that SCN5A variants are actually, in many cases, prognostic rather than diagnostic, resulting in a more severe phenotype. Furthermore, the misconception by some that ajmaline only influences the sodium current is flawed, in that ajmaline actually acts additionally on potassium and calcium currents, as well as mitochondria and metabolic pathways. Clinical studies have implicated several candidate genes in BrS, encoding not only for sodium, potassium, and calcium channel proteins, but also for signaling-related, scaffolding-related, sarcomeric, and mitochondrial proteins. Thus, these proteins, as well as any proteins that act upon them, could prove absolutely relevant in the mechanism of BrS.

[8] Novel SCN5A Variant Shows Multiple Phenotypic Expression in the Same Family

Authors: C. Balla, D. Mele, F. Vitali, C. Andreoli, E. Tonet et al.
Year: 2021
Venue: Circulation. Genomic and Precision Medicine
URL: https://www.semanticscholar.org/paper/4fe4800a3f77d817cbd57f6152fab6fba5688f8f
DOI: 10.1161/CIRCGEN.121.003481
PMID: 34749512
PMCID: 8694256
Citations: 7
Summary: This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.
Evidence snippets:
Snippet 1 (score: 0.438) > To our knowledge, the present case is the first description of an SCN5A variant showing multiple phenotypic expression ranging from Brugada syndrome to ACM in the same family. > Brugada syndrome is an inherited channelopathy first described as a pure electrical disorder predisposing to the risk of sudden cardiac death. Subsequence evidence have shown subtle RV structural abnormalities and RV outflow tract changes leading to different hypothesis on the pathophysiology of the syndrome. 2,3 CM is a genetic heart muscle disorder characterized by fibro-fatty replacement that predispose to ventricular arrhythmias leading to cardiac arrest in young people. > The hypothesis of the close connection between Brugada syndrome and ACM has been supported by the results of Te Riele et al, 4 which show that rare variants in SCN5A are present in ≈2% of patients affected by ACM. Functional analysis of one of the SCN5A mutation showed not only reduced INa amplitude but also a structural deficit in the organization of cell adhesion, supporting the hypothesis that voltage-gated sodium 1.5 may channel have different mechanisms causing cardiomyopathy. 4 ultiple mutation-positive family members harboring the same variant show different phenotypes. Factors, such as age, comorbidities, and environmental factors, may modify the effects of the primary genetic defect. Interindividual variability in disease expression may also be due to the inheritance of genetic modifiers that have a role to determine the age of onset, its rate of progression, and incidence of major cardiac events or to protect from the development of the disease. 5 e current family adds further evidence about the pleiotropic nature of SCN5A showing how a single SCN5A variant may have different clinical expression in the same family.

[9] Sudden death of a patient with epilepsy: When Brugada syndrome mimicry can be fatal

Authors: Gabriele Negro, G. Ciconte, V. Borrelli, R. Rondine, V. Maiolo et al.
Year: 2021
Venue: HeartRhythm Case Reports
URL: https://www.semanticscholar.org/paper/8a91c724330c3814a3156e52911a60db4a637556
DOI: 10.1016/j.hrcr.2021.12.008
PMID: 35492846
PMCID: 9039568
Citations: 3
Influential citations: 1
Summary: are useful in controlling malignant neurologic manifestations, and their adjunctive use in refractory epilepsy reduces mortality 7-fold, and a community-based study found an increased risk of SCD in patients with epilepsy treated with AEDs.
Evidence snippets:
Snippet 1 (score: 0.432) > Brugada syndrome (BrS) is an inherited disorder characterized by coved-type ST-segment elevation in the right precordial leads and increased risk of sudden cardiac death (SCD) in ostensibly normal heart. 1 The electrocardiogram (ECG) manifestations may occur spontaneously or after the exposure to sodium channel blocking agents. 2 The main clinical manifestations (syncope and SCD) are caused by malignant ventricular tachycardia / ventricular fibrillation, which are related to an arrhythmogenic epicardial substrate located in the anterior aspect of the right ventricular outflow tract. 3,4 Idiopathic epilepsy and BrS share the pathophysiology of altered transmembrane ion current caused by mutations of ion channel subunit genes. Sodium channel dysfunction represents a common pathogenetic pathway for these 2 clinical entities that may be involved as a mechanism of sudden death. In addition, mutations of ion channel or arrhythmiarelated genes are the most common defects found in patients experiencing sudden death in epilepsy. 5 Coexistence of epilepsy and BrS in a family with SCN5A mutation has been reported, suggesting that sodium channel mutation may be responsible for cardiac and cerebral manifestations, probably at different ages in the same individual and/or in the same family. 6 The latter underlines the importance of careful assessment of symptoms, detailed family history, and a thorough ECG analysis when evaluating patients with seizure-like symptoms. > Antiepileptic drugs (AEDs) are useful in controlling malignant neurologic manifestations, and their adjunctive use in refractory epilepsy reduces mortality 7-fold. 7 On the other hand, a community-based study found an increased risk of SCD in patients with epilepsy treated with AEDs, and this risk was specifically associated with the use of sodium channel blockers. 8 Among sodium channel blockers used as AEDs, phenytoin (which belongs to the IB class of antiarrhythmic drugs) has been described to induce a type 1 ECG Brugada pattern at supratherapeutic doses. 9 However, its direct role as a trigger of a fatal ventricular arrhythmia in a patient with BrS has never

[10] Brugada Syndrome: Oligogenic or Mendelian Disease?

Authors: M. Monasky, E. Micaglio, G. Ciconte, C. Pappone
Year: 2020
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/79897e2657e5991ed3c7fa322cd57acd0033a832
DOI: 10.3390/ijms21051687
PMID: 32121523
PMCID: 7084676
Citations: 50
Influential citations: 3
Summary: This work has suggested that the best model for studying Brugada syndrome is the human patient population, because there is no mutated gene that connects all, or even a majority, of BrS cases, and it is currently impossible to create animal and cell line genetic models that represent all BrS Cases.
Evidence snippets:
Snippet 1 (score: 0.429) > Brugada syndrome (BrS) is diagnosed by a coved-type ST-segment elevation in the right precordial leads on the electrocardiogram (ECG), and it is associated with an increased risk of sudden cardiac death (SCD) compared to the general population. Although BrS is considered a genetic disease, its molecular mechanism remains elusive in about 70–85% of clinically-confirmed cases. Variants occurring in at least 26 different genes have been previously considered causative, although the causative effect of all but the SCN5A gene has been recently challenged, due to the lack of systematic, evidence-based evaluations, such as a variant’s frequency among the general population, family segregation analyses, and functional studies. Also, variants within a particular gene can be associated with an array of different phenotypes, even within the same family, preventing a clear genotype–phenotype correlation. Moreover, an emerging concept is that a single mutation may not be enough to cause the BrS phenotype, due to the increasing number of common variants now thought to be clinically relevant. Thus, not only the complete list of genes causative of the BrS phenotype remains to be determined, but also the interplay between rare and common multiple variants. This is particularly true for some common polymorphisms whose roles have been recently re-evaluated by outstanding works, including considering for the first time ever a polygenic risk score derived from the heterozygous state for both common and rare variants. The more common a certain variant is, the less impact this variant might have on heart function. We are aware that further studies are warranted to validate a polygenic risk score, because there is no mutated gene that connects all, or even a majority, of BrS cases. For the same reason, it is currently impossible to create animal and cell line genetic models that represent all BrS cases, which would enable the expansion of studies of this syndrome. Thus, the best model at this point is the human patient population. Further studies should first aim to uncover genetic variants within individuals, as well as to collect family segregation data to identify potential genetic causes of BrS.

[11] Mechanisms of Arrhythmias in the Brugada Syndrome

Authors: M. Blok, B. Boukens
Year: 2020
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/cb44ffeb4b14245da88023a83a796a25982dd88a
DOI: 10.3390/ijms21197051
PMID: 32992720
PMCID: 7582368
Citations: 34
Influential citations: 2
Summary: Identifying the site of origin and mechanism of Brugada syndrome would greatly benefit the development of mechanism-driven treatment strategies.
Evidence snippets:
Snippet 1 (score: 0.426) > The human iPSC technology has consistently been employed over the years to allow investigation of the molecular and cellular mechanism of Brugada syndrome in the setting of the native patient-specific cell environment. Despite this major advantage, human iPSC-derived cardiomyocyte models fail to capture the complex changes in tissue architecture that occur in Brugada syndrome. Nevertheless, human iPSC-derived cardiomyocytes are a useful tool to study the functional predisposition to Brugada syndrome. Collectively, these studies led to profound divergent results which could be explained by the variety of genetic mutations studied. In part, the effect of mutations may vary, even if affecting the same gene [144,145]. Furthermore, protocols for human iPSC-derived cardiomyocyte differentiation do not yield a pure cell population of a single type, but rather a variety of cardiomyocytes with divergent phenotypes. In addition, human iPSC-derived cardiomyocytes are characterized by their immature, fetal-like phenotype which, compared to adult cardiomyocytes, consists of different structural and functional properties [146]. > While some studies reported no clear electrophysiological abnormalities in Brugada syndrome patient-derived iPSC-derived cardiomyocyte lines compared to controls [147,148], other reports contrarily showed evidence of significant alterations in action potential duration [65,144], decreased I Na density [65,144,145,[149][150][151], decreased action potential upstroke velocity [65,144,145,150,151], or irregular calcium handling [65,145]. Ma and colleagues found that pacing at a frequency of 0.1 Hz led to a small subgroup (25%) of Brugada syndrome patient-derived iPSC-derived cardiomyocytes presenting with action potentials which were by the authors claimed to resemble the loss of action potential dome configuration as postulated by the repolarization hypothesis, albeit the pacing frequency exceeding human physiological range [71,144]. Only a few studies focus on the potential presence of morphological changes, which were observed by Belbachir and colleagues in the form of cytoskeletal defects [65].

[12] Investigation of a Large Kindred Reveals Cardiac Calsequestrin (CASQ2) as a Cause of Brugada Syndrome

Authors: M. d'Apolito, Francesco Santoro, A. Ranaldi, I. Ragnatela, A. Colia et al.
Year: 2024
Venue: Genes
URL: https://www.semanticscholar.org/paper/7c80f9ec717d86903e5d13270507333e20a7c078
DOI: 10.3390/genes15070822
PMID: 39062601
PMCID: 11275647
Citations: 1
Summary: The data suggest that the p.Tyr178His substitution is associated with BrS in the family investigated, affecting the stability of the protein, disrupting filamentation at the interdimer interface, and affecting the subsequent formation of tetramers and polymers that contain calcium-binding sites.
Evidence snippets:
Snippet 1 (score: 0.421) > Brugada syndrome (BrS) is one of the main hereditary channelopathies characterized by risk of ventricular fibrillation (VF) and sudden cardiac death in an anatomically healthy heart. BrS was first described by Pedro and Josep Brugada in 1992 as a hereditary arrhythmogenic disorder characterized by clinical-electrocardiographic arrhythmia, with a low prevalence globally (0.5 per 1000 or 5 to 20 per 10,000 individuals) [1][2][3]. BrS is found predominantly in men aged between 30 and 40, with a male/female ratio of 9:1 in Southeast Asia and 3:1 among Caucasians [4]. > BrS is characterized by the presence of ST segment elevation in the right precordial leads (V1 to V3), referred to as electrocardiogram (ECG) type I. The diagnosis is established on the existence of spontaneous or drug-induced ST segment elevation characterized by ≥2 mm elevation of the J-point and ST segment, either superiorly convex "arched" (BrS type II) or descending linear (BrS type III). > The ST elevation is followed by a symmetrical negative T wave in ≥1 right and/or high right precordial leads [5,6]. > In spite of the most recent models on further inheritance pathways, BrS is still considered to be an autosomal dominant Mendelian disorder inherited with incomplete penetrance. Genetic mutations have been identified in 11-28% of patients with BrS, with a major percentage affecting the SCN5A (sodium voltage-gated channel alpha subunit 5) gene [7]. Actually, SCN5A is considered the only clinically relevant gene evaluated, even if it is mutated in only about 20% of patients with BrS [7,8]. Pathogenic variations in the SCN5A gene, which encodes the α subunit of the voltage-gated cardiac Na+ channel protein (Nav1.5), were detected in patients with BrS, impairing the proper function of the channel. Genetic variants in over 27 other genes have also been associated with the pathophysiology of BrS.

[13] Molecular Mechanisms of Inherited Arrhythmias

Authors: C. Wolf, C. Berul
Year: 2008
Venue: Current Genomics
URL: https://www.semanticscholar.org/paper/8dc574fc997d6e863ac851b4a75d122de6d9aa61
DOI: 10.2174/138920208784340768
PMID: 19440513
PMCID: 2679644
Citations: 26
Influential citations: 3
Summary: The molecular basis of inherited arrhythmias in structurally normal and altered hearts is summarized, which helps explain the molecular and functional mechanisms of long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and other electrical myopathies.
Evidence snippets:
Snippet 1 (score: 0.420) > Inherited arrhythmias can be life threatening, and are major cause of mortality and morbidity in developed nations. Identification of molecular pathways that increase susceptibility to arrhythmia is necessary to prevent disease occurrence, to improve current therapies and to target new drug development. In recent years, the discovery of pathogenic mutations in inherited arrhythmia syndromes has provided novel insights for the understanding and treatment of diseases predisposing to sudden cardiac death. In patients with the long QT syndromes (LQTS), genotype-phenotype relation studies [1] and genetic testing have influenced patient risk stratification [2] and refined treatment strategies [3]. > Arrhythmia mechanisms include abnormal automaticity, triggered activity, and re-entrant excitation. Each of these mechanisms can occur in any type of myocardial disease or in inherited cardiac arrhythmias. The current article focuses on molecular mechanisms of arrhythmias in the structurally abnormal and normal heart. Hypertrophic and dilated cardiomyopathies, as well as arrhythmogenic right ventricular dysplasia/cardiomyopathy are common substrates of inherited arrhythmias in the structurally abnormal heart. Genetic diseases causing arrhythmias in the structural normal heart, also called electrical myopathies, include the long QT syndromes, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), and non-defined familiar idiopathic ventricular fibrillation. Most, but not all of these disorders are caused by mutations in genes encoding cardiac ion-channel proteins. Among family members carrying an identical mutation in a single gene, remarkable phenotypic variability and expressivity may be observed, suggesting both environmental [4] and genetic modifiers [5].

[14] Natural History of Arrhythmogenic Cardiomyopathy

Authors: G. Mattesi, A. Zorzi, D. Corrado, A. Cipriani
Year: 2020
Venue: Journal of Clinical Medicine
URL: https://www.semanticscholar.org/paper/9d38bdd10019689e9b2ebc49e792f40200041d31
DOI: 10.3390/jcm9030878
PMID: 32210158
PMCID: 7141540
Citations: 38
Influential citations: 2
Summary: The genetic basis, the clinical course and the phenotypic variants of AC are addressed, including non-desmosomal and nongenetic variants reported in patients with AC, some of which showing overlapping phenotypes with other non-ischemic diseases.
Evidence snippets:
Snippet 1 (score: 0.418) > Relationship between arrhythmogenic right ventricular cardiomyopathy (ARVC) and Brugada Syndrome. Mutant desmosomal proteins may induce potentially lethal ventricular arrhythmias by causing gap-junction remodeling and modifying the amplitude and kinetics of the sodium current, as a consequence of the cross-talk between these molecules at the intercalated discs. According to this view, Brugada syndrome and ARVC may share clinical features and arrhythmic mechanisms because of their common origin from the connexome, a coordinated network of proteins involving desmosomes, sodium channels, and gap-junction, aimed to control synergistically adhesion, excitability, and coupling of myocardial cells [18][19][20]. ECG = electrocardiogram; VT = ventricular tachycardia. Modified from Ref [20] with permission of the publisher. > Genes encoding non-desmosomal proteins like ion channels and cytoskeletal components have been also associated with phenotypes within the spectrum of AC, and this may confirm the "final common pathway" hypothesis, by which inherited cardiac diseases with similar phenotype and genetic heterogeneity are due to variants in genes encoding proteins of similar function or involved in a common pathway. According to this view, AC should be considered a disease not only of desmosomes, but of the intercalated disc as a whole [1]. In fact, mutations in transforming grow factor-3 (TFGB3) and in transmembrane protein 43 (TMEM43), which disrupt the desmosomal function, have been detected in patients with classical ARVC [21][22][23], as well as variants in αT-catenin Syndrome. Mutant desmosomal proteins may induce potentially lethal ventricular arrhythmias by causing gap-junction remodeling and modifying the amplitude and kinetics of the sodium current, as a consequence of the cross-talk between these molecules at the intercalated discs. According to this view, Brugada syndrome and ARVC may share clinical features and arrhythmic mechanisms because of their common origin from the connexome, a coordinated network

[15] Genetics of Atrial Fibrillation and Possible Implications for Ischemic Stroke

Authors: R. Lemmens, S. Hermans, D. Nuyens, V. Thijs
Year: 2011
Venue: Stroke Research and Treatment
URL: https://www.semanticscholar.org/paper/0345b2f055b006c87f2022cd3480ec4305266284
DOI: 10.4061/2011/208694
PMID: 21822468
PMCID: 3148589
Citations: 10
Summary: The current knowledge on the genetic background of atrial fibrillation and the consequences for cerebrovascular disease is reviewed.
Evidence snippets:
Snippet 1 (score: 0.413) > The human cardiac sodium channel (SCN5A) is responsible for fast depolarization of cardiomyocytes and has been a therapeutic target for antiarrhythmic drugs. Initially mutations in SCN5A were identified in families with long QT syndrome [8]. Over the years, more than 200 mutations have been reported in SCN5A which are associated with variable cardiac diseases like Brugada syndrome, progressive conduction defect, sick sinus node syndrome, dilated cardiomyopathy and AF [9]. Genotype-phenotype correlations revealed that most mutations are linked to specific clinical spectrums, but that clinical overlaps exist for the same genetic defects [10]. Both Brugada syndrome and long QT syndrome can be complicated with supraventricular arrhythmias which often include AF [11]. More evidence for the role of mutations in SCN5A in the pathophysiology of AF was provided by the identification of a family with a dilated cardiomyopathy and AF carrying a mutation in SCN5A [12]. Additionally, novel mutations in the same gene were reported in familial forms of AF with and without structural cardiac disease [13][14][15][16]. It was determined that rare variants in SCN5A are present in nearly 6% of AF probands [14]. In two studies, functional analysis of the mutation showed a depolarizing shift in steady-state inactivation resulting in cellular hyperexcitability (gain of function) [15,16]. A loss of function was suggested by the study of another variant which revealed a hyperpolarizing shift in steady-state inactivation resulting in prolongation of the atrial action potential duration [13]. This delayed atrial repolarization could induce atrial torsades resulting in AF. Different mechanisms, both loss of function as well as gain of function, have been suggested in various syndromes. Furthermore, there is a wide spectrum of mutations which are associated with overlapping syndromes, suggesting environmental or other genetic factors to be of importance in determining the phenotype.

[16] NaV1.5 autoantibodies in Brugada syndrome: pathogenetic implications

Authors: A. Tarantino, G. Ciconte, D. Melgari, Anthony Frosio, A. Ghiroldi et al.
Year: 2024
Venue: European Heart Journal
URL: https://www.semanticscholar.org/paper/48d95bef9ba5c15b6785ffc2a838788ed411a23e
DOI: 10.1093/eurheartj/ehae480
PMID: 39078224
PMCID: 11491155
Citations: 16
Summary: The presence of anti-NaV1.5 autoantibodies in the majority of BrS patients is demonstrated, suggesting an immunopathogenic component of the syndrome beyond genetic predispositions and prompt reconsideration of the underlying mechanisms of BrS.
Evidence snippets:
Snippet 1 (score: 0.411) > In a significant shift from the translational perspective to Brugada syndrome (BrS), this study highlights the role of autoimmunity by identifying anti-NaV1.5 autoantibodies in affected patients, including those without SCN5A mutations. This discovery is set to complement previous diagnostics based on electrocardiographic manifestations and drug testing and provides a reliable, non-invasive biomarker but also calls for a reevaluation of the pathophysiology of BrS involving immune-mediated mechanisms. The potential of immunomodulatory therapies, especially for genetically elusive cases, may introduce a new era of personalized treatment strategies. > blockers (SCBs), 5 this approach has significant limitations. 6 The pro-arrhythmic potential of such drugs, which are often not available in various countries, and the need for special cardiac monitoring for their administration limit their widespread use. 7 These compounding challenges are ongoing concerns regarding the true specificity and sensitivity of these drug tests. 6 Therefore, the difficulties in consistently detecting the diagnostic ECG pattern associated with the genetic inheritance of BrS 2,8,9 point to an inadequate estimate of the true prevalence of the disease. 0][11][12][13] About 20%-25% of BrS diagnoses are associated with variants in this gene, but the genetic basis for the remaining majority, almost 70%-75%, remains unknown. 14,15 In addition to SCN5A, other genes, including those related to sodium channel β-subunits and potassium and calcium channel genes, have also been investigated for their possible involvement, suggesting a broad and complex genetic basis for the syndrome. 14,15 Nevertheless, the clinical relevance of variations in these additional genes is frequently debated, highlighting the challenges that genetic testing faces in definitively diagnosing a significant proportion of BrS cases. 15,16 To address the complexities associated with genotype-phenotype correlation in BrS, a comprehensive scoring system was developed to aid clinicians identify BrS patients. 2,17 evertheless, the integration of ECG recordings, genetic information, clinical characteristics, and family history into the diagnostic process for BrS is intricate.

[17] Pathogenesis of Brugada Syndrome: -Review from Our Study-

Authors: I. Watanabe
Year: 2018
Venue: Journal of Nihon University Medical Association
URL: https://www.semanticscholar.org/paper/6290fe46092f7b72090ffc16c56cf8de2af4f69b
DOI: 10.4264/NUMA.77.2_77
Summary: This work presents a meta-modelling study of saddleback function and its applications in cardiology and women’s health using a 3D model.
Evidence snippets:
Snippet 1 (score: 0.410) > Pathogenesis of Brugada Syndrome: -Review from Our Study-

[18] Brugada syndrome: current concepts and genetic background

Authors: A. Pérez-Riera, J. Mendes, F. D. Silva, F. Yanowitz, L. D. Abreu et al.
Year: 2021
Venue: Journal of Human Growth and Development
URL: https://www.semanticscholar.org/paper/9703afec4b429fa5ae6a08c66a4249bbc9337705
DOI: 10.36311/JHGD.V31.11074
Citations: 4
Summary: This in depth analytical study of the countless mutations attributed to Brugada syndrome may constitute a real cornerstone that will help to better understand this intriguing syndrome.
Evidence snippets:
Snippet 1 (score: 0.409) > which suggests that parasympathetic tone is a determining factor in arrhythmogenesis: higher level of vagal tone and higher levels of Ito (cardiac transient outward potassium current) is evident during slower heart rates. Although BrS is considered a genetic disease, its mechanism remains unknown in ≈70-75% of cases and no single mutation is sufficient to cause the BrS phenotype. Although ≈20% of patients with BrS carry mutations in SCN5A, which encodes for the pore-forming α subunit of the cardiac sodium channels, the molecular mechanisms underlying this condition are still largely unknown. SCN5A, that was identified as the first BrS-associated gene in 1998, has emerged as the most common gene associated with the syndrome. The SCN5A gene is considered as the only gene definitely associated with BrS. Currently, the oligogenic disease model is the accepted model 1 . More than 400 mutations in the SCN5A gene have been associated with SB. In an evidence-based review of genes reported to cause BS, which are in clinical use, 20 of the 21 genes did not have enough genetic evidence to support their causality for BS. Type 2 Brugada ECG (Electrocardiographic/ Electrocardiogram) pattern has also been associated with mutations in SCN5A (glycerol-3-phosphate dehydrogenase 1-like (GPD1L) protein), which is the domain responsible for a site homologous to SCN5A, and CACNA1C, the gene responsible for the α-subunit of cardiac L-type calcium channels. > To date, mutations of more than 20 genes, other than SCN5A, have been implicated in the pathogenesis of BrS. Multiple pathogenic variants of genes have been shown to alter the normal function of sodium ↓Loss-Of-Function (↓LOF), potassium Gain-Of-Function (↑GOF), and mutations in genes encoding for potassium channels have also been implicated. > Genes influencing I to , include KCNE3, KCND3 and SEMA3A (semaphoring, an endogenous potassium channel inhibitor) while KCNJ8, HCN4, KCN5 and ABCC9 (encoding for SUR2A

[19] Inherited Cardiac Arrhythmia Syndromes: Focus on Molecular Mechanisms Underlying TRPM4 Channelopathies

Authors: M. Amarouch, Jaouad El Hilaly
Year: 2020
Venue: Cardiovascular Therapeutics
URL: https://www.semanticscholar.org/paper/b0b9f5789588a6f6e45f67fe8035b96fef10d183
DOI: 10.1155/2020/6615038
PMID: 33381229
PMCID: 7759408
Citations: 27
Summary: The main objective of this article is to review the major cardiac TRPM4 channelopathies and recent advances regarding their genetic background and the underlying molecular mechanisms.
Evidence snippets:
Snippet 1 (score: 0.407) > The Transient Receptor Potential Melastatin 4 (TRPM4) is a transmembrane N-glycosylated ion channel that belongs to the large family of TRP proteins. It has an equal permeability to Na+ and K+ and is activated via an increase of the intracellular calcium concentration and membrane depolarization. Due to its wide distribution, TRPM4 dysfunction has been linked with several pathophysiological processes, including inherited cardiac arrhythmias. Many pathogenic variants of the TRPM4 gene have been identified in patients with different forms of cardiac disorders such as conduction defects, Brugada syndrome, and congenital long QT syndrome. At the cellular level, these variants induce either gain- or loss-of-function of TRPM4 channels for similar clinical phenotypes. However, the molecular mechanisms associating these functional alterations to the clinical phenotypes remain poorly understood. The main objective of this article is to review the major cardiac TRPM4 channelopathies and recent advances regarding their genetic background and the underlying molecular mechanisms.

[20] Comparative Analysis of Genetic Variations in the Nav1.5 Sodium Channel Subunits that Underlie Brugada Syndrome Using Patient-Specific iPSC-CMs

Authors: Yue Zhu, Linlin Wang, C. Cui, Shaojie Chen, Hongwu Chen et al.
Year: 2020
Venue: Unknown venue
URL: https://www.semanticscholar.org/paper/2728fb811958a39c5487464bc2e9bf7ab604dea9
DOI: 10.21203/rs.3.rs-70177/v1
Summary: Comparison of structural and electrophysiological characteristics of sodium channel subunits with different genetic variations and the safety of quinidine for use with BrS patient-specific iPSC-derived cardiomyocytes provides an advantageous platform for exploring disease mechanisms and evaluating drug safety in vitro.
Evidence snippets:
Snippet 1 (score: 0.400) > Background: Brugada syndrome (BrS) is an autosomal dominant disorder that causes a high predisposition to sudden cardiac death. Several genes have been reported to be associated with BrS. Considering that the heterogeneity in clinical manifestations may result from genetic variations, the application of patient-specific induced pluripotent stem (iPS) cell-derived cardiomyocytes (CMs) may help to reveal cell phenotype characteristics resulting from different genetic backgrounds. The present study was to compare the structural and electrophysiological characteristics of sodium channel subunits with different genetic variations and evaluate the safety of quinidine for use with BrS patient-specific iPSC-derived cardiomyocytes.Methods: Two BrS patient-specific iPS cell lines were constructed that carried missense mutations in SCN5A and SCN1B. One iPS cell line from a healthy volunteer was used as a control. The differentiated cardiomyocytes from the three groups were evaluated by flow cytometry, immunofluorescence staining, electron microscopy, as well as calcium transient and patch clamp analyses to assess different pathological phenotypes. Finally, we evaluated the drug responses to varying concentrations of quinidine by measuring the action potential.Results: Compared to the control group, BrS-CMs showed a significant reduction in sodium current, prolonged action potential duration and varying degrees of decreased Vmax, but no structural difference was observed. After applying different concentrations of quinidine, the disease-specific groups and the control group had a downward trend in maximal upstroke velocity, resting membrane potential and action potential amplitude, and exhibited prolonged action potential duration without increasing incidence of arrhythmic events.Conclusion: Both patient-specific iPSC-CMs recapitulated the BrS phenotype at the cellular level. Although the SCN5A variation led to a markedly lower sodium current than what was observed with the SCN1B variation, their responses to quinidine were quite similar. The present study provides an advantageous platform for exploring disease mechanisms and evaluating drug safety in vitro.

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Brugada Syndrome: Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 68 citations 2026-09-26T14:51:25.019496

Brugada Syndrome: Comprehensive Research Report

1. Disease Overview and Identifiers

Brugada syndrome (BrS) is an inherited primary electrical disease of the heart characterized by a distinctive coved (type 1) ST-segment elevation in the right precordial leads (V1–V3) on a 12-lead electrocardiogram (ECG), occurring in the absence of structural heart disease, and associated with an increased risk of polymorphic ventricular tachycardia, ventricular fibrillation (VF), and sudden cardiac death (SCD), typically during sleep or at rest (GeneReviews — Brugada Syndrome, NCBI Bookshelf; MedlinePlus Genetics). It was first described as a distinct clinical entity by Pedro and Josep Brugada in 1992.

Key identifiers: - OMIM: #601144 (BRGDA1) plus multiple additional locus entries (BRGDA2–BRGDA9+) corresponding to different causal/susceptibility genes (OMIM #601144) - MONDO: MONDO:0015263 - Orphanet: ORPHA:130 - ICD-10-CM: I49.8 (other specified cardiac arrhythmias) — no dedicated Brugada-specific code - ICD-11: BC9Z / related channelopathy codes - MeSH: D053840 (Brugada Syndrome)

Synonyms: Brugada syndrome; BrS; sudden unexplained nocturnal death syndrome (SUNDS, historically linked, particularly in Southeast Asian populations); Pokkuri death syndrome (Japan); right bundle branch block, persistent ST elevation, and sudden death syndrome.

Most published data derive from aggregated disease-level resources (case series, registries such as BRAVO, SADS-TW, FINGER, PRELUDE, and large single- and multi-center cohorts) rather than a single unified EHR-based population; recent large ECG-based population studies (e.g., a 2024 Mayo Clinic 30-year retrospective of >5.3 million ECGs) provide the closest approximation to real-world, individual-level ascertainment (Prevalence and Incidence of Type 1 Brugada Pattern: A 30-Year Experience at Mayo Clinic, 2024).

2. Etiology

2.1 Genetic Causal Factors

BrS is genetically heterogeneous. Although more than 20–23 genes have been reported in association studies, SCN5A (encoding the cardiac sodium channel α-subunit Nav1.5) remains the only gene with robust, clinically actionable evidence for causality, per ClinGen and expert consensus reviews (Annual Review of Genomics and Human Genetics — The Genetics of Brugada Syndrome). SCN5A loss-of-function (LOF) variants are found in roughly 20–25% of clinically diagnosed BrS patients (Cureus 2024; GeneReviews).

Other genes historically implicated but with weaker or now-disputed evidence include: - SCN1B, SCN3B (sodium channel β-subunits) - CACNA1C, CACNB2, CACNA2D1 (L-type calcium channel subunits — associated with a mixed Brugada/short-QT phenotype) - KCNE3, KCNJ8, KCND3 (potassium channel components affecting Ito) - GPD1L, HCN4, RANGRF, SLMAP, TRPM4, PKP2

A large 2023–2025 gene-curation reappraisal by ClinGen substantially deflated the historical "23-gene panel" — most minor genes lack sufficient case-control or functional replication to be considered disease-causing, leaving SCN5A as the sole "definitive" gene (European Journal of Human Genetics 2025).

2.2 Risk Factors

Genetic risk factors: - SCN5A pathogenic LOF variants (missense, nonsense, frameshift, splice-site) causing reduced peak sodium current (INa) - Common susceptibility SNPs at SCN5A-SCN10A (rs11708996, rs10428132) and near HEY2 (rs9388451) — first identified in a 2013 GWAS (Nature Genetics 2013; PubMed 23872634) - A 2022 expanded GWAS meta-analysis of 2,820 BrS cases and 10,001 controls identified 21 association signals at 12 loci (10 novel), with strong SNP-heritability estimates supporting a substantially polygenic architecture layered on top of monogenic SCN5A disease (SADS.org — 2022 Nature Genetics GWAS) - Male sex (prevalence 8–10-fold higher in men than women, attributed in part to greater Ito current density in men, androgen effects, and possibly differential Nav1.5 expression) - Family history of BrS or unexplained sudden death, particularly at a young age

Environmental/acquired risk factors: - Fever — the single most important acute trigger; fever-induced episodes occur in an estimated 20–30% of diagnosed BrS patients, and first clinical manifestation frequently occurs during a febrile illness, especially in children (search synthesis of clinical literature) - Sodium-channel-blocking drugs (Class IA/IC antiarrhythmics, tricyclic antidepressants, some anesthetics/local anesthetics, cocaine) - Excessive alcohol intake, cannabis use - Electrolyte disturbances (hyperkalemia, hypokalemia) - Vagotonic states, bradycardia (sleep, post-prandial states — explaining the classic nocturnal timing of events)

2.3 Protective Factors

Limited literature exists on protective genetic/environmental factors specific to BrS. Gain-of-function polymorphisms increasing INa density and lower Ito expression (relevant to the sex disparity) are inferentially protective; no dedicated protective-variant catalogue analogous to those for coronary disease exists. Avoidance of triggering drugs and prompt fever control are the primary modifiable "protective" behavioral measures (BrugadaDrugs.org).

2.4 Gene-Environment Interactions

The clearest gene-environment interaction is the fever-Nav1.5 relationship: temperature-dependent destabilization of mutant Nav1.5 channel gating/inactivation kinetics (particularly for certain trafficking-defective or fast-inactivating SCN5A variants) unmasks or exacerbates the type 1 ECG pattern and arrhythmic risk during febrile states — "fever worsens sodium channel dysfunction by further reducing conductance" (search synthesis). Drug-gene interactions are similarly central: sodium-channel-blocking agents unmask latent BrS in genetically susceptible individuals via pharmacologic provocation testing (ajmaline, flecainide, procainamide, pilsicainide), which is diagnostically exploited but also constitutes a real-world risk when such drugs are prescribed inadvertently.

3. Phenotypes

3.1 Clinical Signs / Electrocardiographic Phenotype

Type 1 Brugada ECG pattern (the only diagnostic pattern): coved ST-segment elevation ≥2 mm in ≥1 right precordial lead (V1–V2, standard or superior intercostal placement), followed by a negative T wave, occurring spontaneously or after sodium-channel blocker provocation. HPO: consider HP:0025145 (or general "abnormal ST segment"/ECG abnormality terms; BrS lacks a fully specific HPO leaf term for the type-1 coved pattern — bind to the most specific reachable descriptor).
Type 2/3 (saddleback) patterns — non-diagnostic on their own; require provocation testing.
Syncope (HP:0001279) — often due to self-terminating polymorphic VT.
Nocturnal agonal respiration — a classical historical description in SUNDS-overlap cases.
Sudden cardiac death / aborted cardiac arrest (HP:0001645-adjacent / cardiac arrest terms) — may be the first presentation in up to 1/3 of cases.
Palpitations (HP:0001962).
Atrial fibrillation — supraventricular arrhythmia comorbidity reported in ~10–20% of BrS cohorts.
Conduction abnormalities: first-degree AV block, right bundle branch block-like QRS morphology, HV interval prolongation on electrophysiology study.

3.2 Phenotype Characteristics

Age of onset: Typically manifests in adulthood, mean age of sudden death/arrhythmic event in the 3rd–4th decade of life (often cited ~40 years); pediatric presentations occur, usually fever-triggered.
Severity/frequency: Highly variable expressivity — from asymptomatic ECG pattern carriers (common, especially among family members of probands) to malignant, recurrent VF/sudden death.
Progression: Episodic — ECG pattern can be concealed at baseline and unmasked only during fever, drug challenge, or vagotonic states ("dynamic" pattern).
Sex disparity: Prevalence and symptomatic expression are 8- to 10-fold higher in males than females.
Circadian pattern: Arrhythmic events cluster during sleep/nocturnal hours and periods of vagal predominance.

3.3 Quality of Life Impact

Recurrent ICD shocks (appropriate and inappropriate) are a major quality-of-life burden and psychological stressor in BrS cohorts, driving interest in alternative therapies such as quinidine and catheter ablation to reduce shock burden — one driver of the 2023–2024 shift toward epicardial substrate ablation research (BRAVO Registry, Circulation 2023).

4. Genetic/Molecular Information

4.1 Causal Gene

SCN5A (HGNC:10593; chromosome 3p22.2) encoding Nav1.5, the pore-forming α-subunit of the cardiac voltage-gated sodium channel. LOF variants are found in ~20–25% of clinically diagnosed patients (Karger MPP 2024 review).

4.2 Variant Classification and Functional Consequences

Variant types: missense (most common), nonsense, frameshift, splice-site, and occasionally large deletions.
Functional consequence: predominantly loss of function — reduced peak INa via decreased channel trafficking to the membrane, accelerated inactivation, delayed recovery from inactivation, or reduced single-channel conductance.
A 2024–2025 systematic review/meta-analysis (17 studies, 3,568 BrS patients, 3,030 genotyped) confirmed that LOF-type SCN5A variants (versus non-LOF or normal-function variants) are associated with worse arrhythmic prognosis, though the discriminative power is described as only "weak-to-moderate," insufficient for standalone risk stratification (SCN5A variant type-dependent risk prediction in Brugada syndrome, PMC 2025; ResearchGate meta-analysis 2024).
ACMG/ClinVar classification varies widely by variant; functional electrophysiological studies (patch-clamp, heterologous expression) are frequently required to adjudicate variants of uncertain significance (VUS).

4.3 Common/Susceptibility Variants (Polygenic Component)

rs11708996 (SCN5A intronic), rs10428132 (SCN10A), rs9388451 (near HEY2) — the three GWAS-validated common risk SNPs from the original 2013 discovery cohort, combined into a BrS polygenic risk score (BrS-PRS) — likelihood of BrS increases consistently with increasing risk-allele count (Circulation: Genomic and Precision Medicine, SADS-TW validation, PMC; PubMed 32490690).
The expanded 2022 GWAS (2,820 cases/10,001 controls) found 21 signals across 12 loci, and demonstrated that in 2,182 unrelated BrS patients, higher PRS was independently associated with a significantly greater risk of a first life-threatening arrhythmic event since birth — supporting reconceptualization of BrS as a partly polygenic, SCN5A-independent-susceptibility disease (search synthesis, 2022 Nature Genetics).

4.4 Modifier/Regulatory Genes

HEY2 — a Notch-pathway bHLH transcription factor specifically expressed in developing ventricular myocardium; indispensable for ventricular myocyte differentiation, chamber identity, and cardiac morphogenesis. GWAS association with BrS implicates altered transcriptional regulation of ion-channel gene expression during cardiac development, rather than a structural channel defect per se.
SCN10A encodes Nav1.8, historically considered a neuronal channel, but shown to modestly contribute to cardiac INa; LOF SCN10A variants reduce cardiac sodium current.
Established transcriptional regulators of Nav1.5/ion-channel expression relevant to BrS susceptibility: HEY2, TBX20, GATA4, TBX5, IRX3/IRX5.
WT1 — a 2025 preprint identified WT1 as impacting SCN5A expression and cardiac conduction, a novel candidate modifier (bioRxiv 2025).
A rare non-coding enhancer variant in SCN5A was described (medRxiv, 2023) contributing to unusually high BrS prevalence in Thailand — a population-specific regulatory mechanism (medRxiv 2023).

4.5 Epigenetics

Dedicated epigenetic (DNA methylation/histone) studies specific to BrS are sparse in the literature relative to other cardiomyopathies; the primary "epigenetic-adjacent" finding is the transcriptional-regulation angle via HEY2/GATA4/TBX5, i.e., altered developmental gene-regulatory programming of ion channel expression rather than classical postnatal epigenetic marks.

4.6 Chromosomal Abnormalities

BrS is not typically associated with large structural chromosomal rearrangements; it is a channelopathy driven by point variants/small indels in ion channel and channel-regulatory genes, not copy-number disorders.

5. Environmental Information (Triggers and Phenocopy Causes)

5.1 True Trigger Factors (in genetically susceptible individuals)

Fever/febrile illness — the dominant modifiable trigger (see §2.4). Recommended: "12-lead ECG is strongly recommended even in a low-grade fever state in patients belonging to a high-risk group" (search synthesis).
Sodium-channel-blocking drugs across classes: Class IA (ajmaline, procainamide, disopyramide), Class IC (flecainide, propafenone, pilsicainide), tricyclic/tetracyclic antidepressants, some anesthetics/local anesthetics, lithium, and certain anticonvulsants (e.g., lacosamide, implicated in at least one case report during septicemia — PMC 2021).
Cocaine, cannabis, excessive alcohol intake.
Vagotonic states (rest, sleep, the post-prandial period) — mechanistically linked to the nocturnal predominance of events.
Electrolyte disturbances (hyperkalemia).

5.2 Brugada Phenocopy — Reversible, Non-Congenital Mimics

Distinct from true BrS, "Brugada phenocopy" describes reversible Brugada-pattern ECGs arising from an acute, identifiable, non-genetic cause, with normalization once the underlying condition resolves (World Journal of Cardiology 2014, PMC). Documented causes include: - Electrolyte abnormalities (notably hyponatremia — case report/review, PMC 2025: Brugada Phenocopy due to Hyponatremia; also hyperkalemia) - Pulmonary embolism (right ventricular strain/mechanoelectrical feedback) (PubMed 36645685; PubMed 23465226) - Mechanical compression of the right ventricle/RVOT (mediastinal tumors, pectus excavatum — PMC 2021) - Myocardial ischemia or coronary vasospasm - Myocarditis/pericarditis, and infective processes such as empyema (PMC 2025) - Poor ECG lead placement/filter artifact (a technical, not physiologic, phenocopy)

This distinction (phenocopy vs. true congenital BrS) is the basis for the differential-diagnosis addition just made to the Brugada_Syndrome.yaml entry in this repository's working branch.

5.3 Infectious Agents

No infectious agent is causal for true BrS; infection acts only indirectly via fever as a trigger, or via phenocopy mechanisms (myocarditis, sepsis-associated electrolyte/metabolic derangement).

6. Mechanism / Pathophysiology

Causal chain (numbered, from initiating lesion to clinical manifestation)

A germline SCN5A (or, less commonly, another ion-channel/channel-regulatory gene) loss-of-function variant reduces functional Nav1.5 channel density or gating efficiency at the cardiomyocyte membrane, via impaired trafficking, accelerated inactivation, or reduced conductance.
This reduces peak inward sodium current (INa), most prominently in the right ventricular epicardium and RVOT, a region with intrinsically lower INa density and higher transient outward potassium current (Ito) density than the endocardium or left ventricle ("interventricular differences in sodium current" — PMC 2018).
Reduced INa, combined with relatively unopposed Ito-mediated phase-1 repolarization, causes loss of the action potential (AP) "dome" in a subpopulation of RVOT epicardial cells — this occurs heterogeneously, not uniformly, across the epicardial surface.
Heterogeneous dome loss produces marked transmural and epicardial dispersion of repolarization between adjacent sites that retain versus lose the AP dome (the "repolarization hypothesis," now the better-supported of the two classical mechanistic hypotheses — Cardiovascular Research review; JSR literature review 2024).
The voltage gradient between dome-maintaining and dome-losing regions drives electrotonic current flow ("current-load mismatch"), which manifests on the surface ECG as the coved ST-segment elevation in V1–V3 (type 1 Brugada pattern) — this is the mechanistic substrate for the diagnostic ECG sign itself.
Under further destabilizing conditions (fever, sodium-channel-blocking drugs, vagotonic bradycardia), the dome can propagate from a site where it is maintained into an adjacent site where it has been lost, generating a local re-excitation event via phase 2 reentry (Yan and Antzelevitch, 1999) — a closely coupled extrasystole arising from the epicardial dispersion substrate (PMC — Basis for Tissue-Level Phase-2 Reentry).
When three functionally distinct regions coexist in 2D/3D myocardial tissue (a region of delayed dome, a region of lost dome, and normal epicardium), the phase-2-reentrant extrasystole can degenerate into sustained reentrant circuits, producing polymorphic ventricular tachycardia that can deteriorate into ventricular fibrillation.
VF causes hemodynamic collapse and, if untreated, sudden cardiac death — the terminal clinical manifestation of the pathway; events cluster during sleep/vagal-predominant states because vagotonia further reduces INa/ICa,L balance and favors dome loss.

Branch — the depolarization/structural hypothesis (partially supported, competing/complementary): In parallel, an alternative or contributory mechanism proposes that conduction delay in the RVOT — attributable to region-specific myocardial fibrosis and reduced connexin-43 gap-junction density, sometimes with abnormal neural crest cell migration during development — produces fractionated, delayed local activation that itself generates the ST-elevation pattern and arrhythmic substrate independent of, or in addition to, dome-loss repolarization abnormalities (Cardiovascular Research, Amsterdam UMC; ScienceDirect 2010). Current consensus (2024 literature) leans toward the repolarization hypothesis as the predominant/best-experimentally-supported mechanism, based on genetically engineered experimental models reproducing the phenotype, while acknowledging the depolarization/current-load-mismatch and structural (fibrosis/connexin) contributions are not mutually exclusive and likely coexist to varying degrees across patients ("depolarization disorder, repolarization disorder, or more?" — Oxford Academic Cardiovascular Research).

Ajmaline's mechanism (relevant to diagnostic provocation and disease modeling): Beyond pure INa blockade, ajmaline also modulates potassium and calcium currents and mitochondrial/metabolic pathways; combined sodium- and calcium-current blockade in experimental models reproduces loss of the epicardial AP dome, ST elevation, phase 2 reentry, and spontaneous polymorphic VT/VF — an effect that can be normalized by 4-aminopyridine (an Ito blocker), directly implicating Ito in the repolarization mechanism (Frontiers in Cardiovascular Medicine 2021).

Molecular/cellular detail relevant to curation

Molecular pathway/GO terms: cardiac muscle cell action potential (GO:0086001); regulation of cardiac muscle cell membrane repolarization; sodium ion transmembrane transport (GO:0035725); ventricular cardiac muscle cell action potential (GO:0086005).
Protein dysfunction: Nav1.5 (UniProt Q14524) misfolding/trafficking defect or altered gating kinetics; a subset of variants are dominant-negative, reducing wild-type channel surface expression via heteromultimerization.
Cell types (CL terms): cardiac ventricular epicardial myocyte (relevant CL terms for right ventricular/RVOT cardiomyocyte); Purkinje fiber cells have also been implicated as an arrhythmogenic trigger source in some substrate-mapping studies.
Tissue damage/structural correlate: Epicardial mapping studies (BRAVO, UNCOVER(BrS)) directly visualize a fibrotic, low-voltage, fractionated-electrogram arrhythmogenic substrate localized to the anterior RVOT epicardium in symptomatic patients — the direct anatomic target of catheter ablation therapy (Heart Rhythm 2016).
Single-cell/omics: No large-scale single-cell transcriptomic atlas specific to human BrS myocardium was identified in this search; most molecular profiling data derive from iPSC-CM electrophysiology and heterologous expression systems rather than patient-tissue omics.

7. Anatomical Structures Affected

Organ level: Heart — primarily right ventricle, specifically the right ventricular outflow tract (RVOT) epicardium; this is the near-universal localization of both the ECG abnormality and the ablatable arrhythmogenic substrate.
System: Cardiovascular system.
Tissue/cell level: Ventricular epicardial myocardium (RVOT); Purkinje conduction system component in some substrate models.
Subcellular level: Plasma membrane (Nav1.5 channel localization, particularly lateral/T-tubule membrane subdomains — a 2020 study found specific decrease of Na+ channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in BrS, PMC 2020).
Localization/laterality: Right-sided/RVOT predominant — the electrical and structural abnormality is not diffusely biventricular, a key anatomic feature distinguishing it from most cardiomyopathies. UBERON: right cardiac ventricle; cardiac outflow tract.

8. Temporal Development

Onset: Typically adult-onset clinically (mean age at first arrhythmic event roughly 40 years), though the underlying channelopathy is congenital/present from birth; pediatric presentation occurs, usually fever-triggered, and neonatal/infant presentations are described but less common.
Onset pattern: Episodic/paroxysmal — clinical events (syncope, VF) are discrete, unpredictable episodes rather than a continuous progressive process.
Course: The ECG phenotype itself can be dynamic/concealed, fluctuating between normal, type 2/3, and type 1 patterns depending on autonomic tone, temperature, and drug exposure — this "concealed" nature complicates diagnosis and longitudinal risk assessment.
Progression: Not a degenerative or progressive structural disease in the classic sense (no progressive myocardial loss/scarring analogous to cardiomyopathies), though the epicardial fibrotic substrate identified on mapping may itself be age- or disease-duration related in some patients.
Critical periods: Febrile illness (especially in childhood), and periods of high vagal tone (sleep, rest, post-prandial) represent windows of heightened arrhythmic vulnerability.

9. Inheritance and Population Genetics

9.1 Epidemiology

ECG pattern prevalence: ~0.12–0.8% of the general population shows a Brugada-type ECG pattern (mostly non-diagnostic type 2/3) (search synthesis).
Syndrome prevalence: Commonly cited as ~1:2,000 to 1:5,000, with regional variation.
A 2024 Mayo Clinic 30-year retrospective of 5,381,186 ECGs from 2,304,809 patients found 150 patients with at least one ECG showing a type 1 Brugada pattern — of these, 76.0% met BrS criteria, 62.0% were spontaneous, 18.7% fever-induced, and 10.7% drug-induced (Mayo Clinic study, 2024).
A 2024 community-based ECG screening study from Kerala, South India found overall Brugada-pattern prevalence of 1.06% (0.04% type I, 1.01% type II/III) (doaj.org, Indian Heart Journal 2024).
Higher background prevalence is reported in Southeast Asia (Thailand, Philippines, Japan), historically overlapping with the sudden unexplained nocturnal death syndrome (SUNDS) literature; a 2023 study attributes part of Thailand's elevated prevalence to a population-enriched SCN5A regulatory (enhancer) variant (medRxiv 2023).

9.2 Inheritance Pattern

Autosomal dominant in the majority of monogenic (SCN5A-positive) cases; the exception is KCNE5-related BrS, inherited in an X-linked manner (search synthesis of GeneReviews content).
Mendelian (autosomal dominant) transmission is detectable in fewer than 25% of all clinically confirmed cases — the majority of cases either lack an identifiable monogenic cause or reflect a more complex, partly polygenic architecture (the SCN5A-SCN10A-HEY2 common-variant burden plus the broader 2022 GWAS 12-locus signal) (Annual Review of Genomics and Human Genetics summary).
Penetrance: Reduced and age- and sex-dependent; even within SCN5A-positive families, many mutation carriers remain asymptomatic throughout life, and expressivity is highly variable — "reduced penetrance and variable expressivity are hallmarks of Brugada syndrome."
Sex ratio: ~8–10:1 male predominance in symptomatic disease expression, despite equal transmission of the causal variant to both sexes.
Founder effects: Documented in specific populations (e.g., the Thai SCN5A enhancer variant).

9.3 Population Demographics

Higher prevalence/clinical recognition in East and Southeast Asian populations relative to European-ancestry populations.
Predominantly diagnosed in young to middle-aged males (peak clinical presentation 30s–40s).
Family/cascade screening is standard once a proband is identified, given autosomal dominant transmission and the value of identifying at-risk relatives before a sentinel arrhythmic event.

10. Diagnostics

10.1 Diagnostic ECG Criteria

Type 1 Brugada pattern — coved ST elevation ≥2 mm in ≥1 of V1–V2 (standard or high intercostal-space lead placement), spontaneously or after provocation — is the only ECG pattern considered diagnostic.
Pharmacologic provocation testing: Used when resting ECG shows a non-diagnostic (type 2/3, saddleback) pattern in a patient with clinical suspicion. Intravenous ajmaline is the preferred agent internationally, though its limited availability (particularly in the US) has driven increased use of oral or IV flecainide; procainamide and pilsicainide are also used (search synthesis). A 2023 diagnostic refinement — the r′-wave algorithm — was proposed to help predict a positive sodium-channel-blocker provocation test result (PMC 2023).
Fever provocation: A spontaneous or fever-induced type 1 pattern is itself diagnostic; a 12-lead ECG is recommended during febrile episodes in patients from high-risk families or with a suggestive history. A 2025 MDPI paper specifically examined type 1 Brugada pattern triggered by low-grade fever and its diagnostic/risk-stratification implications (MDPI IJMS 2025; PubMed 42123485).

10.2 Genetic Testing

Single-gene (SCN5A) or targeted arrhythmia/channelopathy gene panel testing is recommended following a clinical BrS diagnosis, primarily to enable cascade family screening.
Given only ~20–25% diagnostic yield for SCN5A and the now-limited actionable-gene list post-ClinGen reappraisal, a negative genetic test does not exclude BrS, and genetic results should not independently drive risk stratification or ICD decisions.
Whole-exome/genome sequencing is used mainly in research or when panel testing is non-diagnostic in a strongly phenotype-positive family.

10.3 Electrophysiology Study / Risk Stratification Testing

Programmed ventricular stimulation (PVS): Historically used for risk stratification; a pooled analysis found induced arrhythmia was associated with cardiac events during follow-up (HR 2.66), greatest with single/double extrastimuli (PubMed 26797467). However, more recent literature (2024–2025) questions its predictive value in specific subgroups — PVS did not predict cardiac events in elderly BrS patients in a large Japanese cohort (PMC 2025), and current guidelines do not support PVS specifically in drug-induced type 1 BrS, where SCD risk stratification remains especially challenging. A commentary explicitly asks whether PVS risk prediction is "closing time" (Revista Española de Cardiología 2021).
Non-invasive ECG risk markers (2024–2025 focus): β-angle, fragmented QRS, S wave in lead I, early repolarization pattern, the aVR sign, and quantified transmural dispersion of repolarization have shown predictive value for arrhythmic events and are increasingly emphasized as adjuncts/alternatives to invasive PVS (Frontiers in Cardiovascular Medicine 2025 mini-review; Journal of Interventional Cardiac Electrophysiology 2025).

10.4 Differential Diagnosis

Distinguishing true congenital BrS from Brugada phenocopy (see §5.2) is a core diagnostic step — phenocopies are reversible and resolve with treatment of the underlying cause (correcting electrolytes, treating PE, draining an effusion/empyema, resolving ischemia), whereas true BrS is a lifelong genetic predisposition requiring ongoing risk management.

11. Outcome/Prognosis

BrS is a recognized major cause of sudden cardiac death in patients under 50 years old, particularly in populations without coronary artery disease.
Overall risk stratification remains a major unmet clinical challenge — the majority of BrS carriers (especially those identified through family screening, without prior symptoms) have a relatively benign course, while a minority experience life-threatening arrhythmic events, and current tools imperfectly separate these groups (Frontiers in Cardiovascular Medicine 2025).
Established higher-risk features: spontaneous (vs. drug-induced) type 1 pattern, prior aborted cardiac arrest or documented VF, unexplained syncope, family history of sudden death, male sex, and (per 2024 JACC data) certain nonmodifiable risk factors shown to independently predict outcomes (JACC 2024; JACC 2024 — Risk Stratification: Selecting the Population of Interest).
ICD complication burden: A major driver of current management controversy — ICDs are highly effective at preventing SCD but are associated with substantial complication rates (inappropriate shocks, lead failure, infection) in this typically younger patient population, motivating research into risk-stratified, ICD-sparing strategies (quinidine, catheter ablation).

12. Treatment

12.1 Device Therapy

Implantable cardioverter-defibrillator (ICD) remains the only therapy with proven mortality benefit in high-risk BrS patients (recurrent VF, aborted SCD, high-risk PVS/ECG markers). NCIT: consider NCIT:C15329 (Surgical Procedure) for implantation, with therapeutic_modality: DEVICE.

12.2 Pharmacotherapy

Quinidine (Class IA antiarrhythmic, Ito blocker) — Class IIa indication for BrS patients with electrical storm or recurrent appropriate ICD shocks; shown to significantly reduce shock burden in patients with malignant ventricular arrhythmia episodes (JACC 2016; Circulation). CHEBI: quinidine (CHEBI:28593).
Isoproterenol (IV infusion) — used acutely for electrical storm suppression by increasing ICa,L and restoring the epicardial AP dome.
Antipyretics — prompt fever treatment is considered one of the most effective, low-risk preventive interventions in BrS patients (BrugadaDrugs.org).
Drugs to avoid (comprehensively catalogued at BrugadaDrugs.org, a physician-curated reference): sodium-channel blockers including ajmaline, flecainide, propafenone, procainamide, pilsicainide, allapinin, ethacizin; certain tricyclic antidepressants; cocaine; excessive alcohol; and, per case reports, agents such as lacosamide in the context of critical illness (Medscape treatment overview; PMC 2021 lacosamide case).

12.3 Catheter Ablation (Major Area of 2023–2025 Development)

Epicardial substrate ablation targeting the anterior RVOT arrhythmogenic substrate has emerged as an important adjunct/alternative therapy, particularly for ICD-refractory or ICD-refusing patients:

BRAVO Registry (Brugada Ablation of VF Substrate Ongoing Multicenter Registry, Circulation 2023): catheter ablation of the epicardial substrate is safe and effective at preventing VF recurrence in high-risk BrS patients; VF burden fell from 1.1 ± 2.1 episodes/month pre-ablation to 0.003 ± 0.14 episodes/month post-ablation (p < 0.0001) (Circulation 2023).
A 2024 study of patients with symptomatic BrS who declined ICD implantation found catheter ablation (performed in 66.7% of the cohort) associated with significantly better arrhythmic outcomes than ICD alone (primary outcome 5.6% vs. 54.5%, log-rank p = 0.012) over a median 46.2-month follow-up (EP Europace 2024).
UNCOVER(BrS) study (2024) demonstrated feasibility and preliminary safety of epicardial substrate ablation via a hybrid mini-thoracotomy approach, with no symptomatic arrhythmic recurrences at 12-month follow-up (PMC 2024).
A 2023 systematic review/meta-analysis discusses the "future direction" of substrate-based ablation across inherited primary arrhythmia syndromes including BrS (Journal of Arrhythmia 2023).
Ongoing debate: whether RVOT epicardial substrate ablation should become standard of care in high-risk BrS remains actively discussed in the literature (PMC commentary).

12.4 Genetic/Precision Approaches

A registered clinical trial (NCT07039123) is evaluating a polygenic risk score to optimize primary prevention (ICD candidacy) in intermediate-risk BrS populations — an active translational research direction bridging the 2022 GWAS findings into clinical decision-making (ClinicalTrials.gov).

13. Prevention

Primary prevention: Avoidance of known pharmacologic and physiologic triggers (sodium-channel-blocking drugs, cocaine, excessive alcohol); prompt antipyretic treatment of fever.
Secondary prevention: Cascade genetic and clinical (ECG ± provocation) screening of first-degree relatives of a BrS proband, given autosomal-dominant transmission.
Genetic counseling: Recommended for all confirmed BrS families given the dominant inheritance pattern, reduced penetrance, and variable expressivity — counseling should explicitly address that a child's risk of inheriting a familial pathogenic variant may functionally translate to less than full disease expression due to penetrance/environmental modifiers.
Risk stratification-guided prophylaxis: ICD implantation in confirmed high-risk patients (prior VF/aborted SCD); quinidine as pharmacologic prophylaxis in select intermediate/high-risk patients or those with recurrent ICD shocks.
Public health / point-of-care: Physician and patient education resources (e.g., BrugadaDrugs.org) function as a de facto prophylactic tool by preventing inadvertent prescription of triggering medications.

14. Other Species / Comparative Biology

No robust naturally occurring veterinary BrS phenotype analogous to the human disease is well established in the literature surveyed; most cross-species data come from engineered models rather than natural companion-animal or wildlife disease. Orthologous Scn5a is well conserved across mammals (mouse, canine, porcine), enabling the modeling described below, but naturally occurring inherited canine/feline Brugada-like disease was not identified in this search.

15. Model Organisms

Murine (mouse) models: Scn5a knockout or knock-in of specific human BrS-associated point mutations are used to replicate a generic or family-specific BrS phenotype; heterozygous Scn5a-null mice reproduce conduction slowing and arrhythmia susceptibility, though homozygous knockout is embryonic lethal (search synthesis).
Zebrafish (Danio rerio) models: Increasingly used given cardiac electrophysiological similarities to humans; valuable both for gene-editing (CRISPR) disease modeling and for chemical/drug screening in BrS (Reviews in Cardiovascular Medicine 2024; PMC 2024).
Human iPSC-derived cardiomyocytes (iPSC-CMs): Considered the best current in vitro model for complex inherited arrhythmia syndromes like BrS because they retain the patient's genetic background; used to study Nav1.5 trafficking/gating defects, drug responses, and to test candidate therapeutics (IJMS 2021, PMC; PubMed 33802229).
Heterologous expression systems: HEK293 cells transfected with wild-type or mutant SCN5A/Nav1.5 constructs remain the primary system for detailed biophysical/patch-clamp characterization of variant functional consequences (used to classify VUS as LOF, GOF, or neutral).
Model limitations: Species-specific differences in cardiac electrophysiology (e.g., differing ion channel current densities and repolarization reserve between rodents and humans) limit direct translational extrapolation from murine models; iPSC-CMs, while patient-specific, retain relative electrophysiological immaturity (fetal-like phenotype) compared to adult human cardiomyocytes, a limitation widely acknowledged in the iPSC-CM literature.

Summary of Key Ontology Term Suggestions for Curation

Domain	Suggested term
Disease	MONDO:0015263 (Brugada syndrome)
Causal gene	hgnc:10593 (SCN5A)
Modifier/susceptibility loci	SCN10A (hgnc:10582), HEY2 (hgnc:16116)
Phenotype	Syncope (HP:0001279); Ventricular fibrillation (HP:0001663); Sudden death (search HPO for exact leaf term)
Molecular function	protein-coding voltage-gated sodium channel activity (GO:0005248)
Biological process	cardiac muscle cell action potential (GO:0086001); ventricular cardiac muscle cell action potential (GO:0086005)
Cell type	cardiac ventricular myocyte (search CL for RV/epicardial specificity)
Anatomy	right cardiac ventricle / right ventricular outflow tract (UBERON)
Chemical/drug	quinidine (CHEBI:28593); flecainide, ajmaline (as trigger/provocation agents)
Treatment	NCIT:C15986 (Pharmacotherapy) + therapeutic_agent quinidine; NCIT surgical/device term for ICD; catheter ablation term

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome	Count
References checked	37
Resolved	37
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	2
Quoted claims found in source	0
Quoted claims not found in source	2
References weighed for topical relevance	37
On topic	26
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMID:42123485 (abstract only): "fever worsens sodium channel dysfunction by further reducing conductance"
closest text in source: "Fever worsens sodium channel dysfunction, as elevated temperature further reduces their conductance"
PMID:42123485 (abstract only): "12-lead ECG is strongly recommended even in a low-grade fever state in patients belonging to a high-risk group"
closest text in source: "During the patient's subfebrile episodes, 12-lead ECG recordings revealed ST-segment elevations in leads V1-V3"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	15
Resolved	13
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	7
Terms named correctly	5
Terms named as a different term	0
Terms whose name is worth a second look	2

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

GO:0086001 (2 mentions) - the report calls it "Molecular pathway/GO terms: cardiac muscle cell action potential"; GO calls it cardiac muscle cell action potential**
GO:0005248 (1 mention) - the report calls it "protein-coding voltage-gated sodium channel activity"; GO calls it voltage-gated sodium channel activity

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

13 of 15 terms resolved to a current term; the rest could not be looked up either way.

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Discussions and Knowledge Gaps

Pathophysiology

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Phenotypes

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References & Deep Research

References

Deep Research

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Brugada syndrome. Core disease mechanisms, molecular and cellular pathways...

Relevant Papers

[1] Single Cell Transcriptomics Trajectory and Molecular Convergence of Clinically Relevant Mutations in Brugada Syndrome.

[2] Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patient

[3] Sudden cardiac death and inherited channelopathy: the basic electrophysiology of the myocyte and myocardium in ion channel disease

[4] Electrophysiological Mechanisms of Brugada Syndrome: Insights from Pre-clinical and Clinical Studies

[5] Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

[6] J wave syndrome: Benign or malignant?

[7] The Mechanism of Ajmaline and Thus Brugada Syndrome: Not Only the Sodium Channel!

[8] Novel SCN5A Variant Shows Multiple Phenotypic Expression in the Same Family

[9] Sudden death of a patient with epilepsy: When Brugada syndrome mimicry can be fatal

[10] Brugada Syndrome: Oligogenic or Mendelian Disease?

[11] Mechanisms of Arrhythmias in the Brugada Syndrome

[12] Investigation of a Large Kindred Reveals Cardiac Calsequestrin (CASQ2) as a Cause of Brugada Syndrome

[13] Molecular Mechanisms of Inherited Arrhythmias

[14] Natural History of Arrhythmogenic Cardiomyopathy

[15] Genetics of Atrial Fibrillation and Possible Implications for Ischemic Stroke

[16] NaV1.5 autoantibodies in Brugada syndrome: pathogenetic implications

[17] Pathogenesis of Brugada Syndrome: -Review from Our Study-

[18] Brugada syndrome: current concepts and genetic background

[19] Inherited Cardiac Arrhythmia Syndromes: Focus on Molecular Mechanisms Underlying TRPM4 Channelopathies

[20] Comparative Analysis of Genetic Variations in the Nav1.5 Sodium Channel Subunits that Underlie Brugada Syndrome Using Patient-Specific iPSC-CMs

Notes

Brugada Syndrome: Comprehensive Research Report

1. Disease Overview and Identifiers

2. Etiology

2.1 Genetic Causal Factors

2.2 Risk Factors

2.3 Protective Factors

2.4 Gene-Environment Interactions

3. Phenotypes

3.1 Clinical Signs / Electrocardiographic Phenotype

3.2 Phenotype Characteristics

3.3 Quality of Life Impact

4. Genetic/Molecular Information

4.1 Causal Gene

4.2 Variant Classification and Functional Consequences

4.3 Common/Susceptibility Variants (Polygenic Component)

4.4 Modifier/Regulatory Genes

4.5 Epigenetics

4.6 Chromosomal Abnormalities

5. Environmental Information (Triggers and Phenocopy Causes)

5.1 True Trigger Factors (in genetically susceptible individuals)

5.2 Brugada Phenocopy — Reversible, Non-Congenital Mimics

5.3 Infectious Agents

6. Mechanism / Pathophysiology

Causal chain (numbered, from initiating lesion to clinical manifestation)

Molecular/cellular detail relevant to curation

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population Genetics

9.1 Epidemiology

9.2 Inheritance Pattern

9.3 Population Demographics

10. Diagnostics

10.1 Diagnostic ECG Criteria

10.2 Genetic Testing

10.3 Electrophysiology Study / Risk Stratification Testing

10.4 Differential Diagnosis

11. Outcome/Prognosis