DiagnosisClinical DiagnosisThe 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.FigureFigure 1. Characteristic ECG in Brugada syndrome. Note presence of ST-segment elevation in leads V₁-V₃, coved type. ANDAt least one of the following Documented ventricular fibrillationSelf-terminating polymorphic ventricular tachycardiaA family history of sudden cardiac death Coved-type ECGs in family members Electrophysiologic inducibility Syncope or nocturnal agonal respiration AND/ORMutation 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 TestingGenes. Mutations in eight genes (SCN5A, GPD1L, CACNA1C, CACNB2, SCN1B, KCNE3, SCN3B, and HCN4) 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% 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 SyndromeView in own windowGene Symbol / Phenotype Designation% of Brugada Syndrome Attributed to Mutations in This GeneTest MethodMutations DetectedTest AvailabilitySCN5A / Brugada syndrome 115%-30% ^{1Mutation scanning / sequence analysis 2Sequence variants 3ClinicalDeletion / duplication analysis 4Exonic and whole-gene deletions / duplications 5GPD1L / Brugada syndrome 2Sequence analysisSequence variants 3ClinicalCACNA1C / Brugada syndrome 3Sequence analysisSequence variants 3ClinicalDeletion/ duplication analysis 4Exonic and whole-gene deletions / duplications 5CACNB2 / Brugada syndrome 4Sequence analysisSequence variants 3ClinicalSCN1B / Brugada syndrome 5Sequence analysisSequence variants 3ClinicalKCNE3 / Brugada syndrome 6Sequence analysisSequence variants 3ClinicalDeletion / duplication analysis 4Exonic and whole-gene deletions / duplications 5SCN3B / Brugada syndrome 7Sequence analysisSequence variants 3ClinicalDeletion / duplication analysis 4Exonic and whole-gene deletions / duplications 5HCN4 / Brugada syndrome 8Sequence analysisSequence variants 3Clinical1. 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.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.)Interpretation of test resultsFor issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo 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. 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. 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.Genetically Related (Allelic) DisordersNo 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:SCN5ALong 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 HistoryBrugada 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 CorrelationsFew 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].

Differential DiagnosisBrugada 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 Duchenne muscular dystrophy Friedreich ataxia Thiamine deficiency Hypercalcemia Hyperkalemia Cocaine intoxication Mediastinal tumor compressing the right ventricular outflow tract (RVOT) Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) 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 heartSIDS. Brugada syndrome does not usually cause problems at such a young age; however, mutations 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 this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo 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 ManifestationsBrugada 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 ManifestationsQuinidine (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 ComplicationsDuring surgery and in the postsurgical recovery period persons with Brugada syndrome should be monitored by ECG.SurveillanceAt-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 AvoidThe 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 RiskIf 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 InvestigationSearch 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSCN1B19q13​.12Sodium channel subunit beta-1SCN1B homepage - Mendelian genesSCN1BSCN5A3p22​.2Sodium channel protein type 5 subunit alphaGene Connection for the Heart - SCN5A (LQT3)
SCN5A @ LOVD
SCN5A @ ZAC-GGMSCN5ACACNA1C12p13​.33Voltage-dependent L-type calcium channel subunit alpha-1CGene Connection for the Heart - LQT8 (Timothy syndrome) database
CACNA1C @ ZAC-GGM
CACNA1C homepage - Mendelian genesCACNA1CKCNE311q13​.4Potassium voltage-gated channel subfamily E member 3KCNE3 homepage - Mendelian genesKCNE3HCN415q24​.1Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4Gene Connection for the Heart - Sick Sinus Syndrome database
HCN4 homepage - Mendelian genesHCN4SCN3B11q24​.1Sodium channel subunit beta-3SCN3B homepage - Mendelian genesSCN3BGPD1L3p22​.3Glycerol-3-phosphate dehydrogenase 1-like proteinGPD1L homepage - Mendelian genesGPD1LCACNB210p12​.33-p12.31Voltage-dependent L-type calcium channel subunit beta-2CACNB2 homepage - Mendelian genesCACNB2Data 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) View in own window 114205CALCIUM CHANNEL, VOLTAGE-DEPENDENT, L TYPE, ALPHA-1C SUBUNIT; CACNA1C 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 601144BRUGADA SYNDROME 1; BRGDA1 604433POTASSIUM CHANNEL, VOLTAGE-GATED, ISK-RELATED SUBFAMILY, MEMBER 3; KCNE3 605206HYPERPOLARIZATION-ACTIVATED CYCLIC NUCLEOTIDE-GATED POTASSIUM CHANNEL 4; HCN4 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; BRGDA8Molecular Genetic PathogenesisThe 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.SCN5ANormal allelic variants. The genomic sequence encompasses more than 100 kb. The gene comprises 28 exons [Kapplinger et al 2010].Pathologic allelic variants. More than 100 different SCN5A mutations 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. Normal gene product. SCN5A encodes the α subunit of the cardiac sodium channel gene. The protein 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].GPD1L Normal allelic variants. The gene comprises eight exons. Pathologic allelic variants. In 2007, the mutation p.Ala280Val and the novel SIDS-associated mutation p.Glu83Lys were both shown to decrease cardiac I_Na amplitude. The mutation 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].Normal gene product. The genomic sequence encodes 351 amino acids. The protein glycerol 3-phosphate dehydrogenase 1-like (G3PD1L) affects the trafficking of the cardiac Na⁺ channel to the cell surface. CACNA1CNormal allelic variants. The gene comprises 47 exons. Pathologic allelic variants. The association between CACNA1C and Brugada syndrome was established by the finding of two missense mutations in CACNA1C (p.Ala39Val, p.Gly490Arg). 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 (Ca_v1.2). The Ca_v1.2 channel is activated upon depolarization of the cardiomyocyte, and is responsible for the depolarizing influx of calcium, the L-type calcium current (I_CaL). I_CaL 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 Ca_v1.2 subunits in CHO cells, a clearly reduced I_CaL was found in both cases. Thus, the mechanism of Brugada syndrome with these mutations (i.e., decreased depolarizing current during AP) was independent of SCN5A [Antzelevitch et al 2007].CACNB2Normal allelic variants. The gene comprises 14 exons.Pathologic allelic variants. The missense mutation p.Ser481Leu is located in the C-terminal part of Ca_vβ2 close to the Ca_v1.2 binding domain. Normal gene product. The genomic sequence encodes a protein of 660 amino acids. CACNB2 encodes the β2 subunit (Ca_vβ2) of Ca_v1.2, which modifies gating (increasing the I_CaL) and has been associated with Brugada syndrome 4. Ca_vβ2 functions as a chaperone for the α subunit of Ca_v1.2, ensuring its transport to the plasma membrane. It is the dominantly expressed Ca_v1.2 β subunit in the heart. Abnormal gene product. Because the mutation is located in close proximity to the DI–DII linker of Ca_v1.2, interference with the stimulatory role of Ca_vβ2 on I_Ca is a likely pathogenic mechanism for this mutation. The mechanism of Brugada syndrome 4 involves a reduction of the depolarizing I_Ca [Cordeiro et al 2009].SCN1BNormal allelic variants. The gene comprises three exons.Pathologic allelic variants. Three mutations in SCN1B have been identified segregating with arrhythmia. 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. Normal gene product. The genomic sequence encodes a protein of 218 amino acids. SCN1B encodes the β1 subunit of the cardiac sodium channel conducting the I_Na current. In the heart the biophysical function of the β1 subunits and β1b splicing variant is to modify the function of Na_v1.5, by increasing the I_Na (+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].KCNE3Normal allelic variants. The gene comprises two exons.Pathologic allelic variants. The relation between mutations 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 mutation p.Arg99His. When the mutated KCNE3 was coexpressed in CHO cells with K_v4.3 (the α subunit of the I_to channel), an increase in the I_to 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 I_Ks, I_Kr, and I_to.Abnormal gene product. See Pathologic allelic variants.SCN3BNormal allelic variants. The gene comprises five exons.Pathologic allelic variants. A mutation in SCN3B was found associated with Brugada syndrome. Normal gene product. The genomic sequence encodes a protein of 215 amino acids. SCN3B encodes the β3 subunit of the cardiac sodium channel conducting the I_Na current. In the heart the function of the β3 subunit is to modify the function of Na_v1.5 by increasing the I_Na as for the β1 subunit, albeit with another kinetics. Abnormal gene product. When the mutation p.Leu10Pro was expressed in TSA201 cells together with SCN5A and SCN1B, the mutation was found to result in defective trafficking of Na_v1.5 and reduced I_Na [Hu et al 2009].HCN4Normal allelic variants. The gene comprises eight exons.Pathologic allelic variants. An HCN4 mutation that caused abnormal splicing was identified in a symptomatic individual with Brugada syndrome. HCN4 mutations affect channel properties even in the absence of overt clinical findings [Ueda et al 2009].Normal gene product. The HCN4 genomic sequence encodes a protein of 1203 amino acids.