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Brugada Syndrome

Synonym: Sudden Unexpected Nocturnal Death Syndrome

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

Author Information
, MD, PhD
Girona Institute of Biomedical Research (IDIBGI) and School of Medicine
University of Girona
Girona, Spain
, PhD
School of Medicine
University of Girona
Girona, Spain
, MD, PhD
Free University of Brussels
Brussels, Belgium
, MD, PhD
Cardiovascular Institute
Hospital Clinic
University of Barcelona
Barcelona, Spain
, MD, PhD
Heart Institute of Nanchang University
Jiangxi, China

Initial Posting: ; Last Update: April 10, 2014.

Summary

Disease characteristics. Brugada syndrome is characterized by cardiac conduction abnormalities (ST-segment abnormalities in leads V1-V3 on ECG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood; although age at diagnosis ranges from two days to 85 years. 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/testing. Diagnosis is based on clinical findings. Pathogenic variants in 16 genes have been associated with Brugada syndrome: SCN5A, SCN1B, SCN2B, SCN3B, GPD1L, CACNA1C, CACNB2, CACNA2D1, KCND3, KCNE3, KCNE1L (KCNE5), KCNJ8, HCN4, RANGRF, SLMAP, and TRPM4.

Management. 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.

Surveillance: ECG monitoring every one to two years for at-risk individuals with a family history of Brugada syndrome.

Agents/circumstances to avoid: High fever, anesthetics, antidepressant drugs, and antipsychotic drugs with sodium-blocking effects.

Evaluation of relatives at risk: Identification of relatives at risk using ECG 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. Brugada syndrome is inherited in an autosomal dominant manner. Most individuals diagnosed with Brugada syndrome have an affected parent. The proportion of cases caused by de novo mutation is estimated at 1%. Each child of an individual with Brugada syndrome has a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in the family is known.

Diagnosis

Clinical Diagnosis

The diagnosis of Brugada syndrome is confirmed in an individual with the following:

  • Type 1 ECG (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 ECG abnormality.
Figure 1

Figure

Figure 1. Characteristic ECG in Brugada syndrome. Note presence of ST-segment elevation in leads V1-V3, coved type.

AND

  • At least one of the following
    • Documented ventricular fibrillation
    • Self-terminating polymorphic ventricular tachycardia
    • A family history of sudden cardiac death
    • Coved-type ECGs in family members
    • Electrophysiologic inducibility
    • Syncope or nocturnal agonal respiration

AND/OR

  • Mutation of SCN5A, SCN1B, SCN2B, SCN3B, GPD1L, CACNA1C, CACNB2, CACNA2D1, KCND3, KCNE3, KCNE1L (KCNE5), KCNJ8, HCN4, RANGRF, SLMAP, and TRPM4.

The diagnosis of Brugada syndrome should be strongly considered in individuals with either of the two following ECG types:

  • Type 2 ECG (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 ECG following challenge with a sodium channel blocker (considered equivalent to a positive finding for At least one of the following; see above).

    Note: Drug-induced ST-segment elevation to a value greater than 2 mm should raise the possibility of Brugada syndrome when one or more of the clinical criteria are present (see At least one of the following above). Based on current limited knowledge, whether an individual with a negative drug test (i.e., no change observed in the ST segment in response to a sodium channel blocker) has Brugada syndrome is unknown because the sensitivity of the test is 80% with the sodium channel blocker ajmaline and probably lower for the other class 1 blockers [Hong et al 2004b].
  • Type 3 ECG (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 ECG following challenge with a sodium channel blocker (considered equivalent to a positive finding for At least one of the following; see above).

Note: Drug-induced conversion of type 3 ECG to type 2 ECG is inconclusive.

See Figure 2 for a diagnostic algorithm for Brugada Syndrome.

Figure 2

Figure

Figure 2. Diagnostic algorithm for Brugada syndrome

From Berne & Brugada [2012]. Used by permission.

Molecular Genetic Testing

Genes. Pathogenic variants in 16 genes (SCN5A, SCN1B, SCN2B, SCN3B, GPD1L, CACNA1C, CACNB2, CACNA2D1, KCND3, KCNE3, KCNE1L (KCNE5), KCNJ8, HCN4, RANGRF, SLMAP, and TRPM4) are known to cause Brugada syndrome (Table 1). See Table A. Genes and Databases for chromosome locus and protein name for these genes.)

Evidence for further locus heterogeneity. Because only approximately 25%-30% of Brugada syndrome is accounted for by pathogenic variants in the 16 genes mentioned above, additional locus heterogeneity is likely.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Brugada Syndrome

Gene 1 / Phenotype DesignationProportion of Brugada Syndrome Attributed to Pathogenic Variants in This GeneTest Method
SCN5A / Brugada syndrome 115%-30% 2 Mutation scanning / sequence analysis 3, 4
Deletion/duplication analysis 5
SCN1B / Brugada syndrome 5<1%Sequence analysis 4
SCN2B<1%Sequence analysis 4
SCN3B / Brugada syndrome 7<1%Sequence analysis 4
Deletion/duplication analysis 5, 6
GPD1L / Brugada syndrome 2<1%Sequence analysis 4
CACNA1C / Brugada syndrome 3<1%Sequence analysis 4
Deletion/duplication analysis 5, 6
CACNB2 / Brugada syndrome 4<1%Sequence analysis 4
CACNA2D1 <1%Sequence analysis 4
HCN4 / Brugada syndrome 8<1%Sequence analysis 4
KCND3 <1%Sequence analysis 4
KCNE3 / Brugada syndrome 6<1%Sequence analysis 4
Deletion/duplication analysis 5, 6
KCNE1L (KCNE5)<1%Sequence analysis 4
KCNJ8 <1%Sequence analysis 4
RANGRF <1%Sequence analysis 4
SLMAP <1%Sequence analysis 4
TRPM4 <1%Sequence analysis 4

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2. Pathogenic variants in SCN5A have been identified in approximately 15%-30% of individuals with Brugada syndrome [Kapplinger et al 2010].

3. Sequence analysis and mutation scanning of the entire gene can have similar detection frequencies; however, detection rates for mutation scanning may vary considerably between laboratories based on specific protocol used.

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

5. Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. No deletions or duplications involving CACNA1C, KCNE3, or SCN3B as causative of Brugada syndrome have been reported. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

Testing Strategy

To confirm/establish the diagnosis in a proband. In approximately 75% of persons affected by Brugada syndrome the diagnosis is established based on clinical history and ECG results. Molecular genetic testing confirms the diagnosis and may complement clinical testing [Benito et al 2009].

Single gene testing. When molecular genetic testing is performed:

1.

Sequence analysis of SCN5A is completed first as pathogenic variants in this gene are the most common cause of Brugada syndrome.

2.

If no pathogenic variant is identified, sequence analysis of SCN5A, SCN1B, SCN2B, SCN3B, GPD1L, CACNA1C, CACNB2, CACNA2D1, KCND3, KCNE3, KCNE1L, KCNJ8, HCN4, RANGRF, SLMAP, and TRPM4 may be considered; however, the yield is expected to be very low.

Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having Brugada syndrome is use of a multi-gene panel. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest.

Clinical Description

Natural History

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]. 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].

Currently, the most common presentation is that of a man in his 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].

Males in whom sustained ventricular arrhythmias are easily induced and who have a spontaneously abnormal ECG have a poor prognosis (i.e., 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 overlap 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]. Sick sinus syndrome type 2 (SSS2) (OMIM 163800), caused by heterozygous pathogenic variants in HCN4, is characterized by sinus node dysfunction manifest as sinus bradycardia with a tendency to develop paroxysms of atrial fibrillation with age [Baruscotti et al 2010].

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 persons 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 ECG 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 ECG pattern has been associated with sudden cardiac death. The pathophysiologic mechanisms behind this association remain largely unknown.

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

Figure 3

Figure

Figure 3. Proposed risk stratification scheme and recommendations of ICD in patients with Brugada syndrome

From Berne & Brugada [2012]. Used by permission.

  • Inducibility during electrophysiological 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 ECG 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 ECG 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 ECG 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.

  • The degree of ST elevation and the occurrence of arrhythmias were similar between persons with Brugada syndrome with and without an SCN5A pathogenic variant [Morita et al 2009].
  • In general the SCN5A pathogenic variants which cause LQT3 (see Romano-Ward syndrome) are associated with a gain of 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 seems 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].
  • Genetic variants in the SCN5A promoter region may also have a pathophysiologic role in Brugada syndrome:
    • A haplotype of six nucleotide variants has been linked to reduced expression of the sodium current in functional studies. This haplotype, found among persons of Asian origin, could play a role in modulating the expression of Brugada syndrome in this population [Bezzina et al 2006, Ito et al 2006].
    • The combination of the two Brugada syndrome-causing pathogenic variants p.Arg1232Trp and p.Thr1620Met, each of which produces functional but biophysically defective sodium channels by blocking migration of the protein from nucleous to membrane, may explain disease severity [Baroudi et al 2002, Makita et al 2008].
  • Brugada syndrome caused by calcium (Ca2) channel dysfunction does not have conduction slowing, but does exhibit a Brugada-type ECG after administration of ajmaline [Antzelevitch et al 2007].

Penetrance

Among individuals with an SCN5A pathogenic variant:

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

Nomenclature

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).

Prevalence

Brugada syndrome was identified relatively recently; thus, it is difficult to determine its prevalence and population distribution. Further, because the ECG 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 ECGs compatible with Brugada syndrome.
  • A second study of adults in Awa (Japan) showed a prevalence of 0.6% (66:10,420 individuals).
  • In contrast, a third study in Japanese children showed only a 0.0006% (1:163,110) prevalence of ECGs 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 ECG 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 or sudden cardiac death multi-gene panels may include testing for a number of the genes associated with disorders discussed in this section. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest.

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 ECGs 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 ECG, whereas ARVD/C and Brugada syndrome can both give rise to type 2 and type 3 ECGs. Therefore, it is important to distinguish between these two disorders.

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].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to SCN5A-related Brugada syndrome, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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 ECG or type 3 ECG 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].
  • Medical genetics consultation

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; and
  • Hospitalize the patient at least until the ECG 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 ECG.

Surveillance

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

Agents/Circumstances to Avoid

The following can unmask the Brugada syndrome ECG [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

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

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 ECG. If a type I ECG is identified, further investigation is warranted.

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].

Therapies Under Investigation

Search ClinicalTrials.gov 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, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Brugada syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with Brugada syndrome have inherited the pathogenic variant from a parent.
  • A proband with Brugada syndrome may have the disorder as the result of de novo mutation. The proportion of cases caused by de novo mutation is very low (~1%).
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation 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.

Note: 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

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is affected or has the pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%.
  • If a pathogenic variant cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or de novo mutation in the proband. To date, germline mosaicism has not been described in Brugada syndrome.

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

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

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal 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 is the storage of DNA (typically extracted from white blood cells) for possible future use. 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 of affected individuals.

Prenatal Testing

If the pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Requests for prenatal testing for conditions which (like Brugada Syndrome) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variant has been identified.

Resources

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.

  • National Library of Medicine Genetics Home Reference
  • Ramon Brugada Sr. Foundation
    Email: foundation@brugada.org; ramon@brugada.org
  • Canadian SADS Foundation
    9-6975 Meadowvale Town Centre Circle
    Suite 314
    Mississauga Ontario L5N 2V7
    Canada
    Phone: 877-525-5995 (toll-free); 905-826-6303
    Fax: 905-826-9068
    Email: info@sads.ca
  • SADS Australia
    PO Box 19
    Noble Park Victoria 3174
    Australia
    Email: info@sads.org.au
  • SADS UK
    Churchill House
    Horndon Industrial Park
    Suite 6
    West Horndon Essex CM13 3XD
    United Kingdom
    Phone: 01277 811215
    Email: sadsuk@btconnect.com
  • Sudden Arrhythmia Death Syndromes (SADS) Foundation
    508 East South Temple
    Suite #20
    Salt Lake City UT 84102
    Phone: 800-786-7723 (toll-free); 801-531-0937
    Email: sads@sads.org
  • Brugada Syndrome Registry

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

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
SCN1B19q13​.12Sodium channel subunit beta-1SCN1B databaseSCN1B
SCN5A3p22​.2Sodium channel protein type 5 subunit alphaSCN5A @ LOVD
SCN5A @ ZAC-GGM
Gene Connection for the Heart - SCN5A (LQT3)
SCN5A
CACNA1C12p13​.33Voltage-dependent L-type calcium channel subunit alpha-1CCACNA1C @ ZAC-GGM
Gene Connection for the Heart - LQT8 (Timothy syndrome) database
CACNA1C database
CACNA1C
KCNE311q13​.4Potassium voltage-gated channel subfamily E member 3KCNE3 databaseKCNE3
HCN415q24​.1Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4Gene Connection for the Heart - Sick Sinus Syndrome database
HCN4 database
HCN4
SCN3B11q24​.1Sodium channel subunit beta-3SCN3B databaseSCN3B
GPD1L3p22​.3Glycerol-3-phosphate dehydrogenase 1-like proteinGPD1L databaseGPD1L
CACNB210p12​.33-p12.31Voltage-dependent L-type calcium channel subunit beta-2CACNB2 databaseCACNB2
TRPM419q13​.33Transient receptor potential cation channel subfamily M member 4TRPM4 databaseTRPM4
KCNJ812p12​.1ATP-sensitive inward rectifier potassium channel 8 KCNJ8
SCN2B11q23​.3Sodium channel subunit beta-2 SCN2B
CACNA2D17q21​.11Voltage-dependent calcium channel subunit alpha-2/delta-1 CACNA2D1
KCND31p13​.2Potassium voltage-gated channel subfamily D member 3KCND3 @ LOVDKCND3
KCNE1LXq23Potassium voltage-gated channel subfamily E member 1-like proteinKCNE1L @ LOVDKCNE1L
RANGRF17p13Ran guanine nucleotide release factor RANGRF
SLMAP3p14​.3Sarcolemmal membrane-associated protein SLMAP

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Brugada Syndrome (View All in OMIM)

114204CALCIUM CHANNEL, VOLTAGE-DEPENDENT, ALPHA-2/DELTA SUBUNIT 1; CACNA2D1
114205CALCIUM CHANNEL, VOLTAGE-DEPENDENT, L TYPE, ALPHA-1C SUBUNIT; CACNA1C
300328POTASSIUM CHANNEL, VOLTAGE-GATED, ISK-RELATED FAMILY, MEMBER 1-LIKE; KCNE1L
600003CALCIUM CHANNEL, VOLTAGE-DEPENDENT, BETA-2 SUBUNIT; CACNB2
600163SODIUM CHANNEL, VOLTAGE-GATED, TYPE V, ALPHA SUBUNIT; SCN5A
600235SODIUM CHANNEL, VOLTAGE-GATED, TYPE I, BETA SUBUNIT; SCN1B
600935POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 8; KCNJ8
601144BRUGADA SYNDROME 1; BRGDA1
601327SODIUM CHANNEL, VOLTAGE-GATED, TYPE II, BETA SUBUNIT; SCN2B
602701SARCOLEMMAL-ASSOCIATED PROTEIN; SLMAP
604433POTASSIUM CHANNEL, VOLTAGE-GATED, ISK-RELATED SUBFAMILY, MEMBER 3; KCNE3
605206HYPERPOLARIZATION-ACTIVATED CYCLIC NUCLEOTIDE-GATED POTASSIUM CHANNEL 4; HCN4
605411POTASSIUM VOLTAGE-GATED CHANNEL, SHAL-RELATED SUBFAMILY, MEMBER 3; KCND3
606936TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY M, MEMBER 4; TRPM4
607954RAN GUANINE NUCLEOTIDE RELEASE FACTOR
608214SODIUM CHANNEL, VOLTAGE-GATED, TYPE III, BETA SUBUNIT; SCN3B
611777BRUGADA SYNDROME 2; BRGDA2
611778GLYCEROL-3-PHOSPHATE DEHYDROGENASE 1-LIKE; GPD1L
611875BRUGADA SYNDROME 3; BRGDA3
611876BRUGADA SYNDROME 4; BRGDA4
612838BRUGADA SYNDROME 5; BRGDA5
613119BRUGADA SYNDROME 6; BRGDA6
613120BRUGADA SYNDROME 7; BRGDA7
613123BRUGADA SYNDROME 8; BRGDA8

Molecular Genetic Pathogenesis

Table 2. 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
SCN5A
GPD1L
SCN1B
SCN3B
SCN2B
Nav1.5
Glycerol-3-P-DH-1
Navb1
Navb3
Navb2
Sodium-relatedBrS 10
BrS 14
RANGRF
SLMAP
RAN-G-release factor
Sarcolemma associated protein
PotassiumBrS 6
BrS 8
BrS 9
BrS 11
BrS 12
KCNE3
KCNJ8
HCN4
KCNE1L
KCND3
MiRP2
Kv6.1
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
CACNA1C
CACNB2
CACNA2D1
TRPM4
Cav1.2
Voltage-dependent b-2
Voltage-dependent a2/d1
Transient receptor potential M4

BrS = Brugada syndrome

1. Author, personal communication

SCN5A

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 Symbol.

Pathogenic allelic 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 mutations affecting the structure, function, and trafficking of the sodium channel have been identified.

Table 3. SCN5A Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.845G>Ap.Arg282His 1NM_198056​.2
NP_932173​.1
c.1535C>Tp.Thr512Ile 1
c.3694C>Tp.Arg1232Trp 1
c.4859C>Tp.Thr1620Met 1

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

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. See Genotype-Phenotype Correlations

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). S4 segments are probably the voltage sensors and are 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. It is a tetrodotoxin-resistant Na+ channel isoform. The channel is responsible for the initial upstroke of the action potential in the ECG. 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. The common feature is the decrease in Na+ current availability by two main mechanisms: lack of expression of the mutant channel or accelerated inactivation of the channel [Benito et al 2009]. The identification 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.

SCN1B

Gene structure. The gene comprises three coding exons. SCN1B transcripts were expressed in the human heart and were abundant in Purkinje fibers that play a critical role in electric pulse conduction in heart. The longer transcript NM_001037.4 encodes the shorter isoform (a) NP_001028.1. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Three pathogenic variants that segregated with arrhythmia in families have been identified.

Normal gene product. The genomic sequence encodes a protein of 218 amino acids (isoform a). SCN1B encodes the β1 subunit of the cardiac sodium channel conducting the INa current. In the heart the biophysical function of the β1 subunits and β1b splicing variant is to modify the function of Nav1.5, by increasing the INa (+69% and +76%, respectively).

Abnormal gene product. Electrophysiologic study of heterologously expressed sodium channels revealed loss of sodium current with mutant subunits [Watanabe et al 2008].

SCN2B

Gene Structure. The transcript NM_004588.4 has 4 exons.

Pathogenic allelic variants. See locus specific and HGMD databases in Table A, Haug et al [2000], Watanabe et al [2009], and Riuró et al [2013]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Normal gene product.

The transcript NM_004588.4 encodes the sodium channel subunit beta-2 with 215 amino acids (NP_004579.1).

Abnormal gene product. See Riuró et al [2013].

SCN3B

Gene structure. The gene comprises five coding exons (NM_018400.3). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. A pathogenic variant in SCN3B was found associated with Brugada syndrome [Hu et al 2009].

Table 4. SCN3B Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change Protein Amino Acid ChangeReference Sequences
c.29T>Cp.Leu20ProNM_018400​.3
NP_060870​.1

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

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The genomic sequence encodes a protein of 215 amino acids (NP_060870.1). SCN3B encodes the β3 subunit of the cardiac sodium channel conducting the INa current. In the heart the function of the β3 subunit is to modify the function of Nav1.5 by increasing the INa as for the β1 subunit, albeit with another kinetics.

Abnormal gene product. When the mutant protein with p.Leu10Pro was expressed in TSA201 cells together with SCN5A and SCN1B, the mutant protein was found to result in defective trafficking of Nav1.5 and reduced INa [Hu et al 2009].

GPD1L

Gene structure. The GPD1L transcript NM_015141.3 has 4068 nucleotides and comprises eight exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. In 2007, the pathogenic variant c.839C>T and the novel SIDS-associated pathogenic variant c.247G>A were both shown to decrease cardiac INa amplitude. The pathogenic variant c.839C>T (p.Ala280Val) reduces inward sodium currents by approximately 50% and SCN5A cell surface by approximately 31% [London et al 2007, Van Norstrand et al 2007]. GPDIL pathogenic variant c.839C>T is linked to Brugada syndrome in a large pedigree in which Brugada syndrome is associated with progressive conduction disease, a low sensitivity to procainamide, and a relatively good prognosis [London et al 2007, Van Norstrand et al 2007].

Table 5. GPDIL Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.247G>Ap.Glu83LysNM_015141​.3
NP_055956​.1
c.839C>T 1p.Ala280Val

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

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. SIDS-associated pathogenic variant

Normal gene product. The gene encodes a protein of 351 amino acids (NP_055956.1). The protein glycerol 3-phosphate dehydrogenase 1-like (G3PD1L) affects the trafficking of the cardiac Na+ channel to the cell surface.

Abormal gene product . The G3PD1L protein containing the p.Ala280Val substitution results in a partial reduction of INa caused, at least in part, by a trafficking defect.

CACNA1C

Two other genes associated with the Brugada syndrome encode the α1 (CACNA1C) and β (CACNB2) subunits of the L-type cardiac calcium channel. The pathogenic variants in the α1 and β2b subunits of the cardiac calcium channel were often found to be associated with a familial sudden cardiac death (SCD) syndrome in which a Brugada syndrome phenotype is combined with shorter than normal QT secondary to a loss of function of the calcium channel current (ICa).

Gene structure. The transcript variant NM_000719.6 comprises 47 exons. Multiple alternative transcripts have been described. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants

Table 6. CACNA1C Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.116C>Tp.Ala39Val 1NM_000719​.6
NP_000710​.5
c.1468G>Ap.Gly490Arg 1

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

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Antzelevitch et al [2007]

Normal gene product. The genomic sequence encodes a protein of 2221 amino acids. CACNA1C encodes a number of isoforms of the pore-forming α1 subunit of the long-lasting (L-type) voltage-gated calcium channel (Cav1.2). The Cav1.2 channel is activated upon depolarization of the cardiomyocyte, and is responsible for the depolarizing influx of calcium, the L-type calcium current (ICaL). ICaL inactivates very slowly; thus, it is of major significance for maintaining the plateau phase of the AP. Furthermore, it is the most important source of intracellular calcium and it represents the coupling between excitation and contraction by inducing release of calcium from the sarcoplasmic reticulum through calcium activation of the ryanodine receptors.

Abnormal gene product. When expressed with other Cav1.2 subunits in CHO cells, a clearly reduced ICaL was found in both cases. Thus, the mechanism of Brugada syndrome with these pathogenic variants (i.e., decreased depolarizing current during AP) was independent of SCN5A [Antzelevitch et al 2007].

CACNB2

Gene structure. The transcript NM_201590.2 comprises 13 exons. Alternatively spliced variants encoding different isoforms have been described. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. The missense variant c.1442C>T is located in the region of the gene that encodes the C-terminal part of Cavβ2 close to the Cav1.2 binding domain.

Table 7. CACNB2 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.1442C>Tp.Ser481LeuNM_201590​.2
NP_963884​.2

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

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The genomic sequence encodes a protein of 660 amino acids. CACNB2 encodes the β2 subunit (Cavβ2) of Cav1.2, which modifies gating (increasing the ICaL) and has been associated with Brugada syndrome 4. Cavβ2 functions as a chaperone for the α subunit of Cav1.2, ensuring its transport to the plasma membrane. It is the dominantly expressed Cav1.2 β subunit in the heart.

Abnormal gene product. Because the pathogenic variant is located in close proximity to the DI–DII linker of Cav1.2, interference with the stimulatory role of Cavβ2 on ICa is a likely pathogenic mechanism for this pathogenic variant. The mechanism of Brugada syndrome 4 involves a reduction of the depolarizing ICa [Cordeiro et al 2009].

CACNA2D1

Gene structure. The longest transcript NM_001110843.1 comprises 39 exons and encodes the longest isoform NP_001104313.1 which has 1103 amino acids. Alternatively spliced transcript variants have been described. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants and normal and abnormal gene products. For descriptions see locus-specific and HGMD databases in Table A, Antzelevitch et al [2007], Burashnikov et al [2010], Pérez-Riera et al [2012], and Risgaard et al [2013].

KCND3

Giudicessi et al [2011] provided the first molecular and functional evidence implicating novel gain-of-function KCND3 mutations (Kir4.3 protein) in the pathogenesis and phenotypic expression of Brugada syndrome, with the potential for a lethal arrhythmia being precipitated by a genetically enhanced Ito current gradient within the right ventricle where kcnd3 expression is the highest.

Gene structure. The longest transcript NM_004980.4 comprises eight exons and encodes a 655-amino acid protein NP_004971.2. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

KCNE3

The Brugada syndrome-related gene KCNE3 encodes MiRP2, a regulatory β subunit of the transient outward potassium channel Ito, which is one of five homologous auxiliary β subunits (KCNE peptides) of voltage-gated potassium ion channels.

Gene structure. The transcript NM_005472.4 comprises three exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. The relation between pathogenic variants in KCNE3 and Brugada syndrome 6 was established in a Danish family with four individuals who had a type 1 Brugada syndrome ECG pattern and normal QT interval and the heterozygous KCNE3 missense pathogenic variant p.Arg99His. When the mutated KCNE3 was coexpressed in CHO cells with Kv4.3 (the α subunit of the Ito channel), an increase in the Ito as well as an accelerated inactivation of the current were observed [Delpón et al 2008].

Normal gene product. The genomic sequence encodes a protein of 103 amino acids. KCNE3 encodes MiRP2, one of five homologous auxiliary β subunits (KCNE peptides) of voltage-gated potassium ion channels. The KCNE peptides modulate several potassium currents in the heart, including IKs, IKr, and Ito.

Abnormal gene product. See KCNE3, Pathogenic allelic variants.

KCNE1L (KCNE5)

Although it is well established that Brugada syndrome has mainly an autosomal pattern of inheritance, mutation of this X-linked gene has been described in one family with Brugada syndrome [Ohno et al 2011].

Gene structure. The transcript NM_012282.2 comprises one exon and encodes a protein of 142 amino acids. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

KCNJ8

Previously related to early repolarization syndrome [Haïssaguerre et al 2009], KCNJ8 was implicated as a novel J-wave syndrome susceptibility gene, mutation in which results in a marked gain of function in the cardiac K(ATP) Kir6.1 channel [Medeiros-Domingo et al 2010].

Gene structure. The transcript XM_005253358.2 encodes a protein of 424 amino acids. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

HCN4

Computer simulation showed that the If channel produced a background current contributing to the action potential repolarization of ventricular cardiomyocytes. The background current was generated by a mixed ion-selectivity for Na+ and K+, and incomplete closure for the deactivation gate of If channels.

Gene structure. The transcript NM_005477.2 comprises eight exons and encodes a protein of 1203 amino acids. Two pseudogenes have been identified on chromosome 15. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. An HCN4 pathogenic variant that caused abnormal splicing was identified in a symptomatic individual with Brugada syndrome. HCN4 pathogenic variants affect channel properties even in the absence of overt clinical findings [Ueda et al 2009].

Abnormal gene product. Computer simulation showed that the If channel produced a background current contributing to the action potential repolarization of ventricular cardiomyocytes. The background current was generated by a mixed ion-selectivity for Na+ and K+, and incomplete closure for the deactivation gate of If channels.

RANGRF

Gene structure. The transcript variant NM_016492.4 represents the shortest transcript and encodes the longest isoform of 186 amino acids. Alternative splicing results in multiple transcripts. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants and normal and abnormal gene products. See descriptions in Olesen et al [2011] and Campuzano et al [2014].

SLMAP

Gene structure. The transcript NM_007159.2 comprises 21 exons and encodes a protein of 811 amino acids. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants and normal and abnormal gene products. See descriptions in Ishikawa et al [2012].

TRPM4

Gene structure. The longest transcript variant NM_017636.3 comprises 25 exons and encodes a protein of 1214 amino acids. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See locus specific and HGMD databases in Table A.

Normal gene product. Ion channel that mediates transport of monovalent cations across membranes resulting in depolarization

Abnormal gene product. See Duthoit et al [2012], Stallmeyer et al [2012], Liu et al [2013], and Mathar et al [2014].

References

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Suggested Reading

  1. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A. Brugada syndrome: report of the second consensus conference. Heart Rhythm. 2005;2:429–40. [PubMed: 15898165]
  2. Brugada P, Brugada R, Brugada J. Should patients with an asymptomatic Brugada electrocardiogram undergo pharmacological and electrophysiological testing? Circulation. 2005;112:279–92. [PubMed: 16009809]
  3. Brugada R, Brugada P, Brugada J. Electrocardiogram interpretation and class I blocker challenge in Brugada syndrome. J Electrocardiol. 2006;39:S115–8. [PubMed: 16934827]
  4. Keating MT, Sanguinetti MC. Familial cardiac arrhythmias. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 203. Available online. Accessed 4-4-14.
  5. Morita H, Nagase S, Miura D, Miura A, Hiramatsu S, Tada T, Murakami M, Nishii N, Nakamura K, Morita ST, Oka T, Kusano KF, Ohe T. Differential effects of cardiac sodium channel mutations on initiation of ventricular arrhythmias in patients with Brugada syndrome. Heart Rhythm. 2009;6:487–92. [PubMed: 19324308]
  6. Morita H, Zipes DP, Morita ST, Lopshire JC, Wu J. Epicardial ablation eliminates ventricular arrhythmias in an experimental model of Brugada syndrome. Heart Rhythm. 2009;6:665–71. [PubMed: 19328041]
  7. Morita H, Zipes DP, Morita ST, Wu J. Genotype-phenotype correlation in tissue models of Brugada syndrome simulating patients with sodium and calcium channelopathies. Heart Rhythm. 2010;7:820–7. [PubMed: 20206324]

Chapter Notes

Author Notes

Gencardio

Cardiovascular Genetics Center, University of Girona
C/Pic de Peguera 11, Parc Cientific i Tecnologic, 17003 Girona (Spain)

Ramon Brugada, MD is Dean of the School of Medicine of the University of Girona (Spain), Director of the Cardiovascular Genetics Center at the Biomedical Institute of Girona, and cardiologist at the Hospital 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

  • 10 April 2014 (me) Comprehensive update posted live
  • 16 August 2012 (cd) Revision: multi-gene 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 to live Web site
  • 31 March 2005 (me) Review posted to live Web site
  • 11 March 2004 (rb) Original submission
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Bookshelf ID: NBK1517PMID: 20301690
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