Brugada syndrome

Genetic MONDO:0015263 Pathograph 17 Show in embeddings browser Cardiac Arrhythmia Channelopathy

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.

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1
Mappings
1
Definitions
6
Pathophys.
5
Phenotypes
1
Gaps
17
Pathograph
1
Genes
3
Medical Actions
2
Subtypes
6
Datasets
2
Models
1
Deep Research
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Classifications

Channelopathy
cardiac channelopathy
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Mappings

MONDO
MONDO:0015263 Brugada syndrome
skos:exactMatch MONDO
Primary MONDO disease identifier for this Brugada syndrome root entry.
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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 (2 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.
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Discussions and Knowledge Gaps

1
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 Relation: this experiment is of type this experiment type This experiment is of type 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 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Patient iPSC-derived cardiomyocytes
Patient-derived and isogenic-corrected iPSC-cardiomyocytes challenged with a temperature ramp.
IPSC DERIVED MODEL
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
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.
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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 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology. right ventricular cardiomyocyte CL:2000046 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves right ventricular cardiomyocyte, annotated with ventricular cardiac muscle cell (CL:2000046). CL:2000046 is a cell type from the Cell Ontology.
membrane depolarization during cardiac muscle cell action potential GO:0086012 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased membrane depolarization during cardiac muscle cell action potential (GO:0086012). GO:0086012 is a biological process from the Gene Ontology. ↓ DECREASED cardiac conduction GO:0061337 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cardiac conduction (GO:0061337). GO:0061337 is a biological process from the Gene Ontology. ↓ DECREASED sodium ion transport GO:0006814 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sodium ion transport (GO:0006814). GO:0006814 is a biological process from the Gene Ontology. ↓ DECREASED
monoatomic ion channel activity GO:0005216 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal monoatomic ion channel activity (GO:0005216). GO:0005216 is a molecular function from the Gene Ontology. ⚠ ABNORMAL
outflow tract of right ventricle UBERON:0005953 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in outflow tract of right ventricle, annotated with outflow part of right ventricle (UBERON:0005953). UBERON:0005953 is an anatomical location from the Uberon multi-species anatomy ontology.
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 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology. right ventricular cardiomyocyte CL:2000046 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves right ventricular cardiomyocyte, annotated with ventricular cardiac muscle cell (CL:2000046). CL:2000046 is a cell type from the Cell Ontology.
cardiac muscle cell action potential GO:0086001 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cardiac muscle cell action potential (GO:0086001). GO:0086001 is a biological process from the Gene Ontology. ⚠ ABNORMAL cardiac conduction GO:0061337 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated cardiac conduction (GO:0061337). GO:0061337 is a biological process from the Gene Ontology. ↕ DYSREGULATED
outflow tract of right ventricle UBERON:0005953 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in outflow tract of right ventricle, annotated with outflow part of right ventricle (UBERON:0005953). UBERON:0005953 is an anatomical location from the Uberon multi-species anatomy ontology.
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 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology. right ventricular cardiomyocyte CL:2000046 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves right ventricular cardiomyocyte, annotated with ventricular cardiac muscle cell (CL:2000046). CL:2000046 is a cell type from the Cell Ontology.
cardiac muscle cell action potential GO:0086001 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cardiac muscle cell action potential (GO:0086001). GO:0086001 is a biological process from the Gene Ontology. ⚠ ABNORMAL cardiac conduction GO:0061337 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated cardiac conduction (GO:0061337). GO:0061337 is a biological process from the Gene Ontology. ↕ DYSREGULATED
outflow tract of right ventricle UBERON:0005953 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in outflow tract of right ventricle, annotated with outflow part of right ventricle (UBERON:0005953). UBERON:0005953 is an anatomical location from the Uberon multi-species anatomy ontology.
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 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
cardiac conduction GO:0061337 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cardiac conduction (GO:0061337). GO:0061337 is a biological process from the Gene Ontology. ⚠ ABNORMAL
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 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves right ventricular cardiomyocyte, annotated with ventricular cardiac muscle cell (CL:2000046). CL:2000046 is a cell type from the Cell Ontology.
SCN5A hgnc:10593 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SCN5A (hgnc:10593). hgnc:10593 is a gene from the HUGO Gene Nomenclature Committee.
cellular response to heat GO:0034605 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cellular response to heat (GO:0034605). GO:0034605 is a biological process from the Gene Ontology. ↑ INCREASED
voltage-gated sodium channel activity GO:0005248 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased voltage-gated sodium channel activity (GO:0005248). GO:0005248 is a molecular function from the Gene Ontology. ↓ DECREASED
outflow tract of right ventricle UBERON:0005953 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in outflow tract of right ventricle, annotated with outflow part of right ventricle (UBERON:0005953). UBERON:0005953 is an anatomical location from the Uberon multi-species anatomy ontology.
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.
Pathograph: causal mechanism network for Brugada syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

5
Cardiovascular 3
Syncope HP:0001279 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Syncope (HP:0001279). HP:0001279 is a phenotype from the Human Phenotype Ontology.
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.
Ventricular fibrillation HP:0001663 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular fibrillation (HP:0001663). HP:0001663 is a phenotype from the Human Phenotype Ontology.
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 HP:0001645 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sudden cardiac death (HP:0001645). HP:0001645 is a phenotype from the Human Phenotype Ontology.
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.
Other 2
Type 1 coved ST-segment elevation Coved type ST segment elevation HP:6000984 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Type 1 coved ST-segment elevation, annotated with Coved type ST segment elevation (HP:6000984). HP:6000984 is a phenotype from the Human Phenotype Ontology.
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.
Polymorphic ventricular tachycardia HP:0031677 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is polymorphic ventricular tachycardia (HP:0031677). HP:0031677 is a phenotype from the Human Phenotype Ontology.
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.
🧬

Genetic Associations

1
SCN5A loss-of-function variants (Causative)
Gene: SCN5A hgnc:10593 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SCN5A (hgnc:10593). hgnc:10593 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 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.
💊

Medical Actions

3
Implantable cardioverter-defibrillator placement
Action: implantable cardioverter-defibrillator placementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is implantable cardioverter-defibrillator placement (NCIT:C80435). NCIT:C80435 is a clinical intervention from the NCI Thesaurus. 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: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: quinidine CHEBI:28593 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses quinidine (CHEBI:28593). CHEBI:28593 is a therapeutic agent from Chemical Entities of Biological Interest.
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 ablationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is epicardial ablation (NCIT:C157843). NCIT:C157843 is a clinical intervention from the NCI Thesaurus. 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.
📊

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.
🧮

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.
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.
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.
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.
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.
  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.
  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.
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.
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.
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.
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 & Deep Research

Deep Research

1
Asta ▸
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.

Notes

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