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

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 in SCN5A, GPD1L, CACNA1C, CACNB2, SCN1B, KCNE3, SCN3B, or HCN4.

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 [above]).

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

See Figure 1 for a characteristic ECG observed in an individual with Brugada syndrome.

Molecular Genetic Testing

Genes. Mutations in eight genes (SCN5A, GPD1L, CACNA1C, CACNB2, SCN1B, KCNE3, SCN3B, and HCN4) are known to cause Brugada syndrome (Table 1). See Table A for chromosome locus and protein name for these genes.)

Evidence for further locus heterogeneity. Because only approximately 25% of Brugada syndrome is accounted for by mutations in the eight genes mentioned above, additional locus heterogeneity is likely. Other genes in which mutation may cause Brugada syndrome have recently been identified; further studies must be performed in order to clarify the associations.

• KCNJ8. Previously related to early repolarization syndrome (ERS) [Haissaguerre et al 2009], KCNJ8 was implicated as a novel J-wave syndrome susceptibility gene and a marker gain of function in the cardiac K_(ATP) Kir6.1 channel by Valdivia et al [2010].
• MOG1. MOG1 can impair the trafficking of Na_v1.5 to the membrane, leading to I_Na reduction and clinical manifestation of Brugada syndrome [Kattygnarath et al 2011].
• 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 I_to current gradient within the right ventricle where kcnd3 expression is the highest.
• 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].

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

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Gene Symbol / Phenotype Designation	% of Brugada Syndrome Attributed to Mutations in This Gene	Test Method	Mutations Detected	Test Availability
SCN5A / Brugada syndrome 1	15%-30% 1	Mutation scanning / sequence analysis 2	Sequence variants 3	Clinical
		Deletion / duplication analysis 4	Exonic and whole-gene deletions / duplications 5
GPD1L / Brugada syndrome 2	<5%	Sequence analysis	Sequence variants 3	Clinical
CACNA1C / Brugada syndrome 3	<5%	Sequence analysis	Sequence variants 3	Clinical
		Deletion/ duplication analysis 4	Exonic and whole-gene deletions / duplications 5
CACNB2 / Brugada syndrome 4	<5%	Sequence analysis	Sequence variants 3	Clinical
SCN1B / Brugada syndrome 5	<5%	Sequence analysis	Sequence variants 3	Clinical
KCNE3 / Brugada syndrome 6	<5%	Sequence analysis	Sequence variants 3	Clinical
		Deletion / duplication analysis 4	Exonic and whole-gene deletions / duplications 5
SCN3B / Brugada syndrome 7	<5%	Sequence analysis	Sequence variants 3	Clinical
		Deletion / duplication analysis 4	Exonic and whole-gene deletions / duplications 5
HCN4 / Brugada syndrome 8	<5%	Sequence analysis	Sequence variants 3	Clinical
Brugada Syndrome Multi-Gene Panels 6				Clinical
Sudden Cardiac Death Multi-Gene Panels 6				Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

2. 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.

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

4. Testing that identifies deletions/duplications not readily 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. See CMA.

5. No deletions or duplications involvingCACNA1C, 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.)

6. 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.

Interpretation of test results

For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband. In approximately 75% of persons with 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 mutations in this gene are the most common cause of Brugada syndrome.

2.

If no mutation is identified, sequence analysis of CACNA1C, SCN1B, KCNE3, and SCN3B 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 (Table 1). See Differential Diagnosis.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in CACNB2, KCNE3, HCN4, or GPD1L.

Other phenotypes have been associated with mutations in the following genes:

SCN5A

• Long QT syndrome 3 (LQT3) (see Romano-Ward syndrome [RWS]) is characterized by QT prolongation and T-wave abnormalities on ECG; these abnormalities are associated with tachyarrhythmias, including the ventricular tachycardia torsade de pointes (TdP), which may cause syncope or degenerate into ventricular fibrillation, resulting in aborted cardiac arrest (if the patient is defibrillated) or sudden death. In several reported families, some relatives had a LQT syndrome phenotype and others had a Brugada syndrome phenotype, supporting the concept that the two disorders are part of a spectrum of "sodium channelopathies" [Bezzina et al 1999, Priori et al 2000b, Veldkamp et al 2000, Grant et al 2002].
• Progressive conduction system disease (PCCD, Lenegre disease, isolated cardiac conduction disease) manifests as slowed intramyocardial conduction and, in some cases, progressive atrioventricular (AV) block from first-degree to complete AV block [Schott et al 1999, Tan et al 2001, Wang et al 2002].

CACNA1C. Timothy syndrome [OMIM 601005] is a rare variant of LQTS with marked QT interval prolongation, often presenting with 2:1 functional atrioventricular block and T wave alternans and syndactyly. It is highly malignant, and 10/17 (59%) of the children reported [Splawski et al 2004] died at a mean age of 2.5 years. Some children with Timothy syndrome also had congenital heart diseases, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism.

SCN1B. Temporal lobe epilepsy and generalized epilepsy with febrile seizures plus type 1 (GEFS+1) [OMIM 604233] can be caused by heterozygous SCN1B mutations [Scheffer et al 2007]. In their study, Scheffer et al [2007] found that the phenotype included: febrile seizures (FS: generalized convulsive seizures occurring with fever between age 3 months and 6 years); febrile seizures plus (FS⁺: FS that continued after age 6 years and/or afebrile generalized tonic-clonic seizures before age 6 years); mild generalized epilepsies and severe epileptic encephalopathies including myoclonic-astatic epilepsy (MAE); and severe myoclonic epilepsy of infancy (SMEI). Inheritance is autosomal dominant.

SCN3B mutations have been associated with atrial fibrillation [Wang et al 2010].

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 mutations 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 mutation 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; however, data are preliminary and, thus, insufficient to develop management guidelines.

• 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 by Meregalli et al [2009], who found that among individuals with an SCN5A mutation, those who were more symptomatic had more ECG signs of conduction slowing, supporting the notion that conduction slowing, mediated by loss-of-function SCN5A mutations, 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 mutation [Morita et al 2009].
• In general the SCN5A mutations that 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, mutations 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 mutations [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 normal 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 mutations 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 mutation:

• Approximately 25% 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).

Evaluations Following Initial Diagnosis

To establish the extent of disease 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].

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].

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 (1) 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 to (2) 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 disease-causing mutation 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

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

• ECG changes have low sensitivity in establishing the diagnosis [Priori et al 2003];
• Identification of individuals at risk allows preventive measures such as avoidance of medications that can induce ventricular arrhythmias;
• Surveillance can then be limited to family members who have the disease-causing mutation [Escárcega et al 2009, Benito et al 2009, Nunn et al 2010].

If the disease-causing mutation 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.

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].

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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

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 disease-causing mutation from a parent.
• A proband with Brugada syndrome may have the disorder as the result of a de novo mutation. The proportion of cases caused by de novo mutations 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 mutation in the proband has been identified) molecular genetic testing.

Note: Although most individuals diagnosed with Brugada syndrome have inherited the mutation 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 a disease-causing mutation, the risk to the sibs of inheriting the mutation is 50%.
• If a disease-causing mutation cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. To date, de novo mutations or germline mosaicism have 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 mutation.

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 disease-causing mutation, 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 mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like Brugada syndrome) do not affect intellect and have 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 decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

The relationship between mutations in SCN5A and Brugada syndrome was identified in 1998. SCN5A, the gene that encodes the α subunit of the cardiac sodium channel, is responsible for the phase 0 of the cardiac action potential. The identification of SCN5A disease-causing mutations and the decrease in availability of sodium current suggest that a shift in the ionic balance in favor of a larger transient outward current (I_to) during phase 1 of the action potential causes the disease.

In addition to SCN5A alterations, mutations in SCN1B (encoding the sodium channel β1 subunit) and SCN3B (encoding the cardiac sodium channel β3 subunit) have recently been described. The sodium current-related genes SCN1B and SCN3B encode small β subunits β1 and β3, respectively, of the Na_v complexes. The β subunits have several functions, including interaction with ankyrin-B and -G. SCN1B encodes the β1 subunit of the cardiac sodium channel conducting the I_Na current. In the heart, the biophysical function of the β1 and β1b subunits is to modify the function of Na_v1.5 by increasing the I_Na. SCN3B encodes the β3 subunit of the cardiac sodium channel conducting the I_Na current.

A second locus on chromosome 3, close to but distinct from SCN5A, has been 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. The gene was identified as GPD1L, encoding the protein glycerol-3-phosphate dehydrogenase 1-like. This GPD1L mutation has been shown to result in a partial reduction of I_Na caused, at least in part, by a trafficking defect.

Two other genes associated with the Brugada syndrome encode the α1 (CACNA1C) and β (CACNB2b) subunits of the L-type cardiac calcium channel. The mutations 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 (I_Ca).

The other Brugada syndrome-related gene identified is KCNE3, encoding MiRP2, a regulatory β subunit of the transient outward potassium channel I_to, which is 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 I_Ks (I_Kr, and possibly I_to).

Another gene related to Brugada syndrome is HCN4. A novel HCN4 mutation that caused abnormal splicing has been described in a symptomatic individual. Computer simulation showed that the I_f 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 I_f channels.

Literature Cited

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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 at www​.ommbid.com. Accessed 8-14-12.
5. 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]
6. 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]
7. 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]

Author Notes

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

• 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