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Brugada Syndrome

Synonym: Sudden Unexpected Nocturnal Death Syndrome

, MD, PhD, , BSc, PhD, , MD, PhD, , MD, PhD, , MD, PhD, and , MD, PhD.

Author Information

Initial Posting: ; Last Update: November 17, 2016.

Estimated reading time: 33 minutes


Clinical characteristics.

Brugada syndrome is characterized by cardiac conduction abnormalities (ST-segment abnormalities in leads V1-V3 on EKG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and the sudden unexpected nocturnal death syndrome (SUNDS), a typical presentation in individuals from Southeast Asia. Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome.


Diagnosis is based on clinical findings and/or by the identification of a heterozygous (or hemizygous in the case of KCNE5 in a male) pathogenic variant in one of 23 genes: ABCC9, CACNA1C, CACNA2D1, CACNB2, FGF12, GPD1L, HCN4, KCND2, KCND3, KCNE5, KCNE3, KCNH2, KCNJ8, PKP2, RANGRF, SCN1B, SCN2B, SCN3B, SCN5A, SCN10A, SEMA3A, SLMAP, and TRPM4.


Treatment of manifestations: Implantable cardioverter defibrillator (ICD) in individuals with a history of syncope or cardiac arrest; isoproterenol for electrical storms.

Prevention of primary manifestations: Quinidine (1-2 g daily). Treatment of asymptomatic individuals is controversial.

Prevention of secondary complication: During surgery and in the postsurgical recovery period persons with Brugada syndrome should be monitored by EKG.

Surveillance: EKG monitoring every one to two years for at-risk individuals with a family history of Brugada syndrome or who have a known pathogenic variant that can lead to Brugada syndrome.

Agents/circumstances to avoid: High fever, anesthetics, antidepressant drugs, and antipsychotic drugs with sodium-blocking effects; class 1 C antiarrhythmic drugs (i.e., flecainide, propafenone) and class 1A agents (i.e., procainamide, disopyramide).

Evaluation of relatives at risk: Identification of relatives at risk using EKG or (if the pathogenic variant in the family is known) molecular genetic testing enables use of preventive measures and avoidance of medications that can induce ventricular arrhythmias.

Genetic counseling.

In most cases Brugada syndrome is inherited in an autosomal dominant manner; the exception is KCNE5-related Brugada syndrome, which is inherited in an X-linked manner. Most individuals diagnosed with Brugada syndrome have an affected parent. The proportion of cases caused by a de novo pathogenic variant is estimated at 1%. Each child of an individual with autosomal dominant Brugada syndrome has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk is possible if the pathogenic variant in the family is known.


Brugada syndrome is a channelopathy, caused by genetic changes in transmembrane ion channels which create action potentials, in this case leading to an increased risk of cardiac arrhythmia [Benito et al 2009].

Suggestive Findings

Brugada syndrome should be suspected in individuals with any of the following findings:

  • Recurrent syncope
  • Ventricular fibrillation
  • Self-terminating polymorphic ventricular tachycardia
  • Cardiac arrest
  • Family history of sudden cardiac death

AND one of the following EKG patterns:

  • Type 1 EKG (elevation of the J wave ≥2 mm with a negative T wave and ST segment that is coved type and gradually descending) in more than one right precordial lead (V1-V3)* (see Figure 1) with or without administration of a sodium channel blocker (i.e., flecainide, pilsicainide, ajmaline, or procainamide)
    * No other factor(s) should account for the EKG abnormality.
  • Type 2 EKG (elevation of the J wave ≥2 mm with a positive or biphasic T wave; ST segment with saddle-back configuration and elevated ≥1 mm) in more than one right precordial lead under baseline conditions with conversion to type 1 EKG following challenge with a sodium channel blocker
  • Type 3 EKG (elevation of the J wave ≥2 mm with a positive T wave; ST segment with saddle-back configuration and elevated <1 mm) in more than one lead under baseline conditions with conversion to type 1 EKG following challenge with a sodium channel blocker
Figure 1. . Characteristic EKG in Brugada syndrome.

Figure 1.

Characteristic EKG in Brugada syndrome. Note presence of ST-segment elevation in leads V1-V3, coved type.

Establishing the Diagnosis

The diagnosis of Brugada syndrome is established in a proband with both of following findings and may include identification of a heterozygous (or hemizygous in the case of KCNE5 in a male) pathogenic variant in one of the genes listed in Tables 1a and 1b (see Note).

  • Type 1 EKG (elevation of the J wave ≥2 mm with a negative T wave and ST segment that is coved type and gradually descending) in more than one right precordial lead (V1-V3)* (see Figure 1) with or without administration of a sodium channel blocker (i.e., flecainide, pilsicainide, ajmaline, or procainamide)
    * No other factor(s) should account for the EKG abnormality.
  • At least one of the following:
    • Documented ventricular fibrillation
    • Self-terminating polymorphic ventricular tachycardia
    • A family history of sudden cardiac death
    • Coved-type EKGs in family members
    • Electrophysiologic inducibility
    • Syncope or nocturnal agonal respiration

Note: In approximately 75% of persons affected by Brugada syndrome the diagnosis is established based on clinical history and EKG results. Molecular genetic testing confirms the diagnosis and may complement clinical testing [Benito et al 2009].

See Figure 2 for a diagnostic algorithm for Brugada syndrome.

Figure 2.

Figure 2.

Diagnostic algorithm for Brugada syndrome From Berne & Brugada [2012]. Used by permission.

Molecular genetic testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Serial single-gene testing can be considered starting with SCN5A, heterozygous pathogenic variants in which account for 15%-30% of cases. Alternatively, serial single-gene testing may be considered if factors including clinical findings, laboratory findings, and ancestry indicate that mutation of a particular gene is most likely.
    Sequence analysis of the gene of interest is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  • A multigene panel that includes all current Brugada syndrome-related and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing and/or use of a multigene panel fails to confirm a diagnosis in an individual with features of Brugada syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

See Table 1a for the most common genetic causes (i.e., pathogenic variants of any one of the genes included in this table account for >1% of Brugada syndrome) and Table 1b for less common genetic causes (i.e., pathogenic variants of any one of the genes included in this table are reported in only a few families).

Table 1a.

Molecular Genetics of Brugada Syndrome: Most Common Genetic Causes

Gene 1Phenotype Designation% of Brugada Syndrome Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 2 Detectable by Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
SCN5A Brugada syndrome 115%-30% 5>95%Unknown 6

Pathogenic variants of any one of the genes included in this table account for >1% of Brugada syndrome.


See Molecular Genetics for information on pathogenic allelic variants detected.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


Table 1b.

Molecular Genetics of Brugada Syndrome: Less Common Genetic Causes

Gene 1 ,2, 3Phenotype Designation
CACNA1C Brugada syndrome 3
CACNB2 Brugada syndrome 4
GPD1L Brugada syndrome 2
HCN4 Brugada syndrome 8
KCNE3 Brugada syndrome 6
SCN1B Brugada syndrome 5
SCN3B Brugada syndrome 7

Pathogenic variants of any one of the genes listed in this table are reported in only a few families (i.e., <1% of Brugada syndrome)


Genes are listed in alphabetic order.


Genes are not described in detail in Molecular Genetics, but may be included here (pdf).

Clinical Characteristics

Clinical Description

Age at diagnosis. Brugada syndrome manifests primarily during adulthood, with a mean age of sudden death of approximately 40 years. The youngest individual diagnosed with the syndrome was two days old and the oldest age 85 years [Huang & Marcus 2004].

Sex differences. Although Brugada syndrome is more prevalent among males, it affects females as well, and both sexes are at a high risk for ventricular arrhythmias and sudden death [Hong et al 2004b].

Presentation. Currently, the most common presentation is that of a person in his/her 40s with malignant arrhythmias and a previous history of syncopal episodes. Syncope is a common presenting symptom [Mills et al 2005, Benito & Brugada 2006, Karaca & Dinckal 2006].

Affected individuals in whom sustained ventricular arrhythmias are easily induced and who have a spontaneously abnormal EKG have a 45% likelihood of having an arrhythmic event at any time during life [Benito et al 2009]. Electrical storms (also known as arrhythmic storms), which are multiple episodes of ventricular arrhythmias that occur over a short period of time, are malignant but rare phenomena in Brugada syndrome. Incessant ventricular tachycardia (VT) is defined as hemodynamically stable VT continuing for hours.

Brugada syndrome can occur in conjunction with conduction disease. The presence of first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome in Brugada syndrome is not unusual [Smits et al 2005].

Clinical presentations of Brugada syndrome may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) [Priori et al 2000a, Antzelevitch 2001, Skinner et al 2005, Van Norstrand et al 2007] and sudden unexpected nocturnal death syndrome (SUNDS) [Vatta et al 2002], a syndrome seen in Southeast Asia in which young people die from cardiac arrest with no identifiable cause. The same pathogenic variant in SCN5A was identified in individuals with Brugada syndrome and SUNDS, thus supporting the hypothesis that they are the same disease [Hong et al 2004a].

Precipitating factors for the Brugada EKG pattern and the syndrome of sudden cardiac death (SCD) include fever, cocaine use, electrolyte disturbances, and use of class I antiarrhythmic medications and a number of other non-cardiac medications [Francis & Antzelevitch 2005]. Most importantly, in some (usually young) persons, the presence of the induced EKG pattern has been associated with sudden cardiac death. The pathophysiologic mechanisms behind this association remain largely unknown.

Predicting risk of malignant arrhythmias. Several parameters have been investigated to improve stratification of the risk of developing malignant arrhythmias (see Figure 3).

Figure 3.

Figure 3.

Proposed risk stratification scheme and recommendations of ICD in individuals with Brugada syndrome From Berne & Brugada [2012]. Used by permission.

  • Inducibility during electrophysiologic study (EPS) is the only parameter currently used for clinical decision making. During such a study the heart is electrically stimulated using intracardiac catheters. Although the inducibility of arrhythmias in an asymptomatic individual during the EPS is highly predictive of subsequent malignant events (arrhythmias and sudden cardiac death), the data remain controversial. Several groups do not use EPS for risk stratification in asymptomatic individuals; however, no other risk stratification parameter is presently available [Nunn et al 2010]. Thus, decisions regarding timing of implantation of a defibrillator vary widely among physicians and investigators [Eckardt et al 2005, Glatter et al 2005, Ikeda et al 2005, Al-Khatib 2006, Delise et al 2006, Gehi et al 2006, Imaki et al 2006, Ito et al 2006, Ott & Marcus 2006, Tatsumi et al 2006, Benito et al 2009].
  • Genotype has been proposed as an additional parameter for risk stratification. Meregalli et al [2009] found that among individuals with an SCN5A pathogenic variant, those who were more symptomatic had more EKG signs of conduction slowing, supporting the notion that conduction slowing, mediated by loss-of-function SCN5A pathogenic variants, was a key pathophysiologic mechanism in Brugada syndrome. This limited study indicates that it may be possible in the future to use genotype information in risk stratification; however, at present this remains an area of investigation.

Pathophysiology. Brugada syndrome, caused by a sodium channelopathy, is associated with age-related progressive conduction abnormalities, such as prolongation of the EKG PQ, QRS, and HV intervals [Smits et al 2002, Yokokawa et al 2007]. Sodium current dysfunction contributes to local conduction block in the epicardium, resulting in multiple spikes within the QRS complex and triggering of atrial and ventricular fibrillation [Morita et al 2008].

Sodium channelopathies exhibited typical Brugada-type EKG and frequent arrhythmogenesis during bradycardia [Makiyama et al 2005]; both quinidine and isoproterenol normalized the J-ST elevation and prevented arrhythmias.

Genotype-Phenotype Correlations

Few studies have investigated genotype-phenotype correlations.

For SCN5A:

  • The degree of ST elevation and the occurrence of arrhythmias were similar between persons with Brugada syndrome with and without a heterozygous SCN5A pathogenic variant [Morita et al 2009].
  • In general the SCN5A pathogenic variants which cause LQT3 (see Long QT Syndrome) are associated with a gain of abnormal function rather than the loss of function associated with Brugada syndrome and progressive conduction system disease; however, pathogenic variants that are associated with both diseases in the same family have been described.
  • By restoring (at least partially) sodium current defects, the common SCN5A variant p.His558Arg appears to modulate the phenotypic effects of heterozygous SCN5A pathogenic variants [Lizotte et al 2009] such as p.Thr512Ile, which results in clinically significant cardiac conduction disturbances [Viswanathan et al 2003], and p.Arg282His, which results in Brugada syndrome [Poelzing et al 2006].


Among individuals with an SCN5A pathogenic variant:

  • Approximately 20%-30% have an EKG diagnostic of Brugada syndrome;
  • Approximately 80% manifest the characteristic EKG changes when challenged with a sodium channel blocker (ajmaline) [Hong et al 2004b, Benito et al 2009].


Vatta et al [2002] and Hong et al [2004a] determined that sudden unexpected nocturnal death syndrome (SUNDS) and Brugada syndrome are phenotypically, genetically, and functionally the same disorder. SUNDS was originally described in individuals from Southeast Asia. Other names for SUNDS include sudden and unexpected death syndrome (SUDS), bangungut (Philippines), non-lai tai (Laos), lai-tai (Thailand), and pokkuri (Japan).


Brugada syndrome was identified relatively recently; thus, it is difficult to determine its prevalence and population distribution. Further, because the EKG is dynamic and may normalize, diagnosis may be problematic, making it difficult to estimate the true incidence of Brugada syndrome in the general population.

Data suggest that Brugada syndrome occurs worldwide. The prevalence of the disease in endemic areas is on the order of 1:2,000 persons. In countries in Southeast Asia in which sudden unexpected nocturnal death syndrome (SUNDS) is endemic, it is the second cause (following accidents) of death of men under age 40 years.

Data from published studies indicate that Brugada syndrome is responsible for 4%-12% of unexpected sudden deaths and for up to 20% of all sudden death in individuals with an apparently normal heart.

As recognition of Brugada syndrome increases in the future, a sizeable increase in the number of identified cases can be expected.

A prospective study of an adult Japanese population (22,027 individuals) showed 12 individuals (prevalence of 0.05%) with EKGs compatible with Brugada syndrome [Tohyou et al 1995].

A second study of adults in Awa (Japan) showed a prevalence of 0.6% (66:10,420 individuals) [Namiki et al 1995].

In contrast, a third study in Japanese children showed only a 0.0006% (1:163,110) prevalence of EKGs compatible with Brugada syndrome [Hata et al 1997]. Therefore, in the absence of symptoms and/or molecular genetic testing of SCN5A, these studies provide an estimate of the prevalence of the Brugada syndrome EKG pattern (not of Brugada syndrome) in the population studied. The results suggest that Brugada syndrome manifests primarily during adulthood, a finding in concordance with the mean age of sudden death (age 35-40 years).

Differential Diagnosis

Brugada syndrome should always be considered in the differential diagnosis of:

  • Sudden cardiac death and syncope in persons with a structurally normal heart
  • SIDS. Brugada syndrome does not usually cause problems at such a young age; however, pathogenic variants in SCN5A have been previously described in a few SIDS cases. SIDS is believed to be etiologically and genetically heterogeneous [Weese-Mayer et al 2007] with an unknown proportion attributed to Brugada syndrome.
  • Sick sinus syndrome. Brugada syndrome could be observed in persons with sick sinus syndrome given the defects observed in cardiac conduction [Nakazato et al 2004].

Other conditions that can be associated with ST-segment elevation in right precordial leads include the following (adapted from Wilde et al [2002] with permission).

Abnormalities that can lead to ST-segment elevation in the right precordial leads

  • Right or left bundle branch block, left ventricular hypertrophy
  • Acute myocardial ischemia or infarction
  • Acute myocarditis
  • Hypothermia, causing Osborn wave in EKGs and sometimes resembling Brugada syndrome
  • Right ventricular ischemia or infarction
  • Dissecting aortic aneurysm
  • Acute pulmonary thromboemboli
  • Various central and autonomic nervous system abnormalities
  • Heterocyclic antidepressant overdose
  • Thiamine deficiency
  • Hypercalcemia
  • Hyperkalemia
  • Cocaine intoxication
  • Mediastinal tumor compressing the right ventricular outflow tract (RVOT)

Other conditions that can lead to ST-segment elevation in the right precordial leads

  • Early repolarization syndrome
  • Other normal variants (particularly in males)

Most of the conditions listed can give rise to a type 1 EKG, whereas ARVD/C and Brugada syndrome can both give rise to type 2 and type 3 EKGs. Therefore, it is important to distinguish between these two disorders.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Brugada syndrome, the following evaluations are recommended:

  • Electrocardiogram
  • Induction with sodium blockers (ajmaline, procainamide, pilsicainide, flecainide) in persons with a type 2 EKG or type 3 EKG and suspicion of the disease
  • Electrophysiologic study to assess risk of sudden cardiac death. Although the data are controversial, no other risk stratification parameter is presently available for asymptomatic individuals [Nunn et al 2010].
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Brugada syndrome is characterized by the presence of ST-segment elevation in leads V1 to V3. Implantable cardioverter defibrillators (ICDs) are the only therapy currently known to be effective in persons with Brugada syndrome with syncope or cardiac arrest [Brugada et al 1999, Wilde et al 2002]. See Figure 3 for risk stratification and recommendations of ICD in individuals with Brugada syndrome.

Electrical storms respond well to infusion of isoproterenol (1-3 µg/min), the first line of therapy before other antiarrhythmics [Maury et al 2004].

It is important to:

  • Eliminate/treat agents/circumstances such as fever, cocaine use, electrolyte disturbances, and use of class I antiarrhythmic medications and other non-cardiac medications that can induce acute arrhythmias;
  • Hospitalize the patient at least until the EKG pattern has normalized.

Controversy exists regarding the treatment of asymptomatic individuals. Recommendations vary [Benito et al 2009, Escárcega et al 2009, Nunn et al 2010] and include the following:

  • Observation until the first symptom develops (the first symptom can also be sudden cardiac death)
  • Placement of an ICD if the family history is positive for sudden cardiac death
  • Use of electrophysiologic study (EPS) to identify those most likely to experience arrhythmias and thus to benefit the most from placement of an ICD

Prevention of Primary Manifestations

Quinidine (1-2 g daily) has been shown to restore ST segment elevation and decrease the incidence of arrhythmias [Belhassen et al 2004, Hermida et al 2004, Probst et al 2006].

Prevention of Secondary Complications

During surgery and in the postsurgical recovery period persons with Brugada syndrome should be monitored by EKG.


At-risk individuals with a family history of Brugada syndrome or a known pathogenic variant should undergo EKG monitoring every one to two years beginning at birth [Oe et al 2005]. The presence of type I EKG changes should be further investigated.

Agents/Circumstances to Avoid

The following can unmask the Brugada syndrome EKG [Antzelevitch et al 2002]:

  • Febrile state
  • Vagotonic agents
  • α-adrenergic agonists [Miyazaki et al 1996]
  • β-adrenergic antagonists
  • Tricyclic antidepressants
  • First-generation antihistamines (dimenhydrinate)
  • Cocaine toxicity

The following should be avoided [Antzelevitch et al 2003]:

  • Class 1C antiarrhythmic drugs including flecainide and propafenone
  • Class 1A agents including procainamide and disopyramide

Evaluation of Relatives at Risk

If the pathogenic variant has been identified in an affected family member, molecular genetic testing of at-risk relatives is appropriate because:

If the pathogenic variant has not been identified in the family, relatives should be screened with an EKG. If a type I EKG is identified, further investigation is warranted.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Hormonal changes during pregnancy can precipitate arrhythmic events in women with Brugada syndrome. Recurrent ventricular tachyarrhythmia can be inhibited and the electrocardiographic pattern can normalize following IV infusion of low-dose isoproterenol followed by oral quinidine [Sharif-Kazemi et al 2011].

Quinidine is not known to be teratogenic to the developing fetus and is a preferred drug to treat arrhythmia in pregnancy. See for more information about medication use during pregnancy.

Therapies Under Investigation

Search in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Brugada syndrome is inherited in an autosomal dominant manner with the exception of one family with Brugada syndrome associated with a pathogenic variant in KCNE5, an X-linked gene [Ohno et al 2011].

Risk to Family Members (Autosomal Dominant Inheritance)

Parents of a proband

  • Most individuals diagnosed with Brugada syndrome have an affected parent.
  • A proband with Brugada syndrome may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants is very low (~1%).
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include electrocardiographic analysis, attention to a family history of sudden death, and (if the pathogenic variant in the proband has been identified) molecular genetic testing.
  • If a pathogenic variant cannot be detected in the DNA of either parent, two possible explanations are a de novo pathogenic variant in the proband or germline mosaicism in a parent (to date, germline mosaicism has not been described in Brugada syndrome).
  • Although most individuals diagnosed with Brugada syndrome have inherited the pathogenic variant from a parent, the family history may appear to be negative because of failure to recognize the disorder in family members, incomplete penetrance, early death of the parent before the onset of symptoms, or late onset of the symptoms in the affected parent.

Sibs of a proband

  • If a parent of the proband is affected, or unaffected but known to be heterozygous for the pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. The risk that a sib with the familial pathogenic variant will develop Brugada syndrome may be less than 50% because of reduced penetrance (see Penetrance).
  • Sibs who do not inherit the variant identified in the proband are at approximately the same risk for Brugada syndrome as the general population due to the possibility of other genetic variants.
  • The sibs of a proband with clinically unaffected parents are still at increased risk for Brugada syndrome because of the possibility of reduced penetrance in a parent (i.e., a clinically unaffected parent may be heterozygous for a pathogenic variant).
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs of inheriting the pathogenic variant is presumed to be <1% (the theoretic risk of parental germline mosaicism).

Offspring of a proband. Each child of an individual with Brugada syndrome has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or has a pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA in whom a molecular diagnosis has not been confirmed (i.e., the causative genetic alteration/s are unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for Brugada syndrome are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Fundación Brugada
    Phone: 34 872 98 70 87 extension 63
  • My46 Trait Profile
  • National Library of Medicine Genetics Home Reference
  • Canadian SADS Foundation
    9-6975 Meadowvale Town Centre Circle
    Suite 314
    Mississauga Ontario L5N 2V7
    Phone: 877-525-5995 (toll-free); 905-826-6303
    Fax: 905-826-9068
  • Sudden Arrhythmia Death Syndromes (SADS) Foundation
    508 East South Temple
    Suite #202
    Salt Lake City UT 84102
    Phone: 800-786-7723 (toll-free); 801-531-0937

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Brugada Syndrome: Genes and Databases

Locus NameGeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
ARVD9 PKP2 12p11​.21 Plakophilin-2 PKP2 @ LOVD
ARVD/C Genetic Variants Database - PKP2
ABCC9 12p12​.1 ATP-binding cassette sub-family C member 9 ABCC9 database ABCC9 ABCC9
CACNA1C 12p13​.33 Voltage-dependent L-type calcium channel subunit alpha-1C CACNA1C database
CACNA2D1 7q21​.11 Voltage-dependent calcium channel subunit alpha-2/delta-1 CACNA2D1 CACNA2D1
CACNB2 10p12​.33-p12.31 Voltage-dependent L-type calcium channel subunit beta-2 CACNB2 database CACNB2 CACNB2
FGF12 3q28-q29 Fibroblast growth factor 12 FGF12 FGF12
GPD1L 3p22​.3 Glycerol-3-phosphate dehydrogenase 1-like protein GPD1L database GPD1L GPD1L
HCN4 15q24​.1 Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 HCN4 database HCN4 HCN4
KCND2 7q31​.31 Potassium voltage-gated channel subfamily D member 2 KCND2 KCND2
KCND3 1p13​.2 Potassium voltage-gated channel subfamily D member 3 KCND3 @ LOVD KCND3 KCND3
KCNE3 11q13​.4 Potassium voltage-gated channel subfamily E member 3 KCNE3 database KCNE3 KCNE3
KCNE5 Xq23 Potassium voltage-gated channel subfamily E regulatory beta subunit 5 KCNE1L @ LOVD KCNE5 KCNE5
KCNH2 7q36​.1 Potassium voltage-gated channel subfamily H member 2 KCNH2 database
KCNJ8 12p12​.1 ATP-sensitive inward rectifier potassium channel 8 KCNJ8 KCNJ8
RANGRF 17p13​.1 Ran guanine nucleotide release factor RANGRF RANGRF
SCN1B 19q13​.11 Sodium channel subunit beta-1 SCN1B database SCN1B SCN1B
SCN2B 11q23​.3 Sodium channel subunit beta-2 SCN2B SCN2B
SCN3B 11q24​.1 Sodium channel subunit beta-3 SCN3B database SCN3B SCN3B
SCN5A 3p22​.2 Sodium channel protein type 5 subunit alpha SCN5A @ LOVD
SCN10A 3p22​.2 Sodium channel protein type 10 subunit alpha SCN10A SCN10A
SEMA3A 7q21​.11 Semaphorin-3A SEMA3A SEMA3A
SLMAP 3p14​.3 Sarcolemmal membrane-associated protein SLMAP SLMAP
TRPM4 19q13​.33 Transient receptor potential cation channel subfamily M member 4 TRPM4 database TRPM4 TRPM4

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Brugada Syndrome (View All in OMIM)


Molecular Pathogenesis

Table 3.

Ion Channels and Associated Brugada Syndrome Phenotype Designations, Genes, and Proteins

ChannelPhenotype Designation 1GeneCommon Protein Names
SodiumBrS 1
BrS 2
BrS 5
BrS 7
BrS 16
Sodium-relatedBrS 10
BrS 14
RAN-G-release factor
Sarcolemma associated protein
PotassiumBrS 6
BrS 8
BrS 9
BrS 11
BrS 12
Hyperpolarization cyclic nucleotide-gated 4
Potassium voltage-gated channel subfamily E member 1-like
Kv4.3 Kir4.3
CalciumBrS 3 and shorter QT
BrS 4 and shorter QT
BrS 13
BrS 15
Voltage-dependent b-2
Voltage-dependent a2/d1
Transient receptor potential M4

BrS = Brugada syndrome


Author, personal communication


Gene structure. The genomic sequence encompasses more than 100 kb. The gene comprises 28 exons [Kapplinger et al 2010]. The longest transcript variant is NM_198056.2; multiple other transcripts have also been identified. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. The relationship between pathogenic variants in SCN5A and Brugada syndrome was identified in 1998. More than 100 different SCN5A pathogenic variants have been reported to date [Moric et al 2003, Tan et al 2003, Kapplinger et al 2010], approximately half of which have been biophysically characterized. Several different pathogenic variants affecting the structure, function, and trafficking of the sodium channel have been identified.

Table 4.

SCN5A Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.845G>Ap.Arg282His 1 NM_198056​.2
c.1535C>Tp.Thr512Ile 1
c.3694C>Tp.Arg1232Trp 1
c.4859C>Tp.Thr1620Met 1

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Normal gene product. SCN5A encodes the α subunit of the cardiac sodium channel and is responsible for the phase 0 of the cardiac action potential. The 2016-amino acid protein (NP_932173.1) contains four internal repeats, each with five hydrophobic segments (S1, S2, S3, S5, S6) and one positively charged segment (S4). The S4 segment is probably the voltage sensor and is characterized by a series of positively charged amino acids at every third position (adapted from Human Genome Browser). This integral membrane protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na+ ions may pass in accordance with their electrochemical gradient. SCN5A is a tetrodotoxin-resistant Na+ channel isoform. The channel is responsible for the initial upstroke of the action potential in the EKG. The protein is expressed in human atrial and ventricular cardiac muscle but not in adult skeletal muscle, brain, myometrium, liver, or spleen.

Abnormal gene product. Pathogenic variants in SCN5A result in a decrease in Na+ current availability by one of two main mechanisms: lack of expression of the mutated channel or accelerated inactivation of the channel [Benito et al 2009]. Characterization of SCN5A pathogenic variants and the decrease in availability of sodium current suggest that a shift in the ionic balance in favor of a larger transient outward current (Ito) during phase 1 of the action potential causes the disease.

For further information on the genes listed in Table 1b, click here.


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Chapter Notes

Author Notes

Cardiovascular Genetics Center, University of Girona
Institut d'Investigacions Biomèdiques de Girona (IDIBGI)
C/ Dr Castany s/n, Parc Hospitalari Martí i Julià (Mancomunitat-2) 17190
Salt -Girona- (Spain)

Ramon Brugada, MD is Professor of Cardiology (School of Medicine, University of Girona), Director of the Cardiovascular Genetics Center, and cardiologist at the Hospital Josep Trueta in Girona.

  • Clinical interest. As a clinical and noninvasive cardiologist, Dr Brugada is interested in the management of patients with inherited disorders of the heart.
  • Research interest. Dr Brugada's research interests are focused on molecular genetics of cardiovascular disease with an emphasis on genetics of cardiac arrhythmias. His research achievements include the identification of the chromosomal locus on 10q22 for familial atrial fibrillation, the gene for familial idiopathic ventricular fibrillation (Brugada syndrome), and the gene for short QT syndrome.

Revision History

  • 17 November 2016 (ma) Comprehensive update posted live
  • 10 April 2014 (me) Comprehensive update posted live
  • 16 August 2012 (cd) Revision: multigene panels for Brugada syndrome and sudden cardiac death available clinically
  • 12 January 2012 (cd) Revision: clinical testing for mutations in CACNB2 and HCN4 now listed in the GeneTests™ Laboratory Directory; large deletion in SCN5A reported [Eastaugh et al 2011]
  • 8 September 2011 (me) Comprehensive update posted live
  • 11 August 2009 (cd) Revision: prenatal testing for SCN5A available clinically
  • 7 December 2007 (me) Comprehensive update posted live
  • 31 March 2005 (me) Review posted live
  • 11 March 2004 (rb) Original submission
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