Clinical characteristics.

Brugada syndrome is characterized by cardiac conduction abnormalities (ST segment abnormalities in leads V₁-V₃ on EKG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood, although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and 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.

The diagnosis of Brugada syndrome is established clinically in an individual with characteristic EKG findings and suggestive clinical history and/or family history. A molecular diagnosis can be established in an individual with characteristic features and identification of a heterozygous pathogenic variant in SCN5A or one of the additional 42 genes associated with Brugada syndrome.

Management.

Treatment of manifestations: Implantable cardioverter defibrillator (ICD) in individuals with a history of syncope or cardiac arrest; isoproterenol for electrical storms. During surgery and in the postsurgical recovery period persons with Brugada syndrome should be monitored by EKG.

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

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

Agents/circumstances to avoid: High fever, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic antagonists, tricyclic antidepressants; first-generation antihistamines (dimenhydrinate); cocaine; class 1C antiarrhythmic drugs (flecainide, propafenone) and class 1A agents (procainamide, disopyramide).

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

Genetic counseling.

In most instances Brugada syndrome is inherited in an autosomal dominant manner; the exception is KCNE5-related Brugada syndrome, which is inherited in an X-linked manner. Most individuals diagnosed with Brugada syndrome have an affected parent or another affected close relative. The proportion of individuals with Brugada syndrome caused by a de novo pathogenic variant is very low (~1%). Each child of an individual with autosomal dominant Brugada syndrome has a 50% chance of inheriting the pathogenic variant. The risk that a child will inherit the familial pathogenic variant and develop Brugada syndrome may be less than 50% because of reduced penetrance and the possibility of other genetic and environmental factors. Reduced penetrance and variable expressivity are hallmarks of Brugada syndrome. Once the Brugada syndrome-related pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for Brugada syndrome are possible.

Suggestive Findings

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

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

AND one of the following EKG patterns:

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

Figure 1.

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

Establishing the Diagnosis

The clinical diagnosis of Brugada syndrome can be established in a proband based on clinical diagnostic criteria, or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous (or hemizygous in the case of KCNE5 in a male) pathogenic (or likely pathogenic) variant in one of the genes listed in Table 1. (See Figure 2 for a diagnostic algorithm for Brugada syndrome.)

Figure 2.

Diagnostic algorithm for Brugada syndrome Reproduced from Berne & Brugada [2012] with permission

Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

Clinical Description

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

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

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

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

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

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

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

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

Figure 3.

Proposed risk stratification scheme and recommendations of ICD in individuals with Brugada syndrome Reproduced from Berne & Brugada [2012] with permission

• Inducibility during electrophysiologic study (EPS) is the only parameter currently used for clinical decision making. During such a study the heart is electrically stimulated using intracardiac catheters. Although the inducibility of arrhythmias in an asymptomatic individual during the EPS is highly predictive of subsequent malignant events (arrhythmias and sudden cardiac death), the data remain controversial. Several groups do not use EPS for risk stratification in asymptomatic individuals. Several multiparametric approaches to determine risk are available. However, their predictive abilities remain modest in individuals with Brugada syndrome and in asymptomatic individuals [Rodríguez-Mañero et al 2022]. Thus, decisions regarding timing of implantation of a defibrillator vary widely among physicians and investigators [Eckardt et al 2005, Glatter et al 2005, Ikeda et al 2005, Al-Khatib 2006, Delise et al 2006, Gehi et al 2006, Imaki et al 2006, Ito et al 2006, Ott & Marcus 2006, Tatsumi et al 2006, Benito et al 2009].
• Genotype has been proposed as an additional parameter for risk stratification. Meregalli et al [2009] found that among individuals with an SCN5A pathogenic variant, those who were more symptomatic had more EKG signs of conduction slowing, supporting the notion that conduction slowing, mediated by loss-of-function SCN5A pathogenic variants, was a key pathophysiologic mechanism in Brugada syndrome. This limited study indicates that it may be possible in the future to use genotype information in risk stratification; however, at present this remains an area of investigation.

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

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

Phenotype Correlations by Gene

SCN5A. The degree of ST elevation and the occurrence of arrhythmias were similar between persons with Brugada syndrome with and without a heterozygous SCN5A pathogenic variant [Morita et al 2009].

Genotype-Phenotype Correlations

Few studies have investigated genotype-phenotype correlations [Ciconte et al 2021].

SCN5A

• In general, the SCN5A pathogenic variants which cause LQT3 (see Long QT 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 appears to modulate the phenotypic effects of heterozygous SCN5A pathogenic variants [Lizotte et al 2009] such as p.Thr512Ile, which results in clinically significant cardiac conduction disturbances [Viswanathan et al 2003], and p.Arg282His, which results in Brugada syndrome [Poelzing et al 2006].

Penetrance

SCN5A. Among individuals with an SCN5A pathogenic variant approximately 20%-30% have an EKG diagnostic of Brugada syndrome; and approximately 80% manifest the characteristic EKG changes when challenged with a sodium channel blocker (e.g., 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 occurs worldwide. The prevalence of the disease in endemic areas (South Asia) is on the order of 1:2,000 persons. In countries in Southeast Asia in which SUNDS is endemic, it is the second leading cause of death (following accidents) 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 [Brugada et al 1999a].

A prospective study of an adult Japanese population (22,027 individuals) showed 12 individuals (prevalence of 0.05%) with EKGs compatible with Brugada syndrome [Tohyou et al 1995]. A second study of adults in Awa, Japan, showed a prevalence of 0.6% (66:10,420 individuals) [Namiki et al 1995]. In contrast, a third study in Japanese children showed only a 0.0006% (1:163,110) prevalence of EKGs compatible with Brugada syndrome [Hata et al 1997]. Therefore, in the absence of symptoms and/or molecular genetic testing, these studies provide an estimate of the prevalence of the Brugada syndrome EKG pattern (not of Brugada syndrome) in the population studied. The results suggest that Brugada syndrome manifests primarily during adulthood, a finding in concordance with the mean age of sudden death (age 35-40 years).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Brugada syndrome, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Electrocardiogram (EKG)
• Induction with sodium blockers (ajmaline, procainamide, pilsicainide, flecainide) in persons with a type 2 EKG or type 3 EKG and suspicion of the disease
• Electrophysiologic study to assess risk of sudden cardiac death. Although the data are controversial, no other risk stratification parameter is presently available for asymptomatic individuals [Nunn et al 2010].
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of Brugada syndrome to facilitate medical and personal decision making

Treatment of Manifestations

Brugada syndrome is characterized by the presence of ST segment elevation in leads V₁-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 1999b, 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 noncardiac medications that can induce acute arrhythmias;
  AND
• Hospitalize the patient at least until the EKG pattern has normalized.

Controversy exists regarding the treatment of asymptomatic individuals. Recommendations vary [Benito et al 2009, Escárcega et al 2009, Nunn et al 2010, Brugada et al 2018] and include the following:

• Observation until the first symptom develops (Note: 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 benefit the most from placement of an ICD

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

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].

Surveillance

At-risk individuals with a family history of Brugada syndrome or a known pathogenic variant should undergo EKG monitoring every one to two years beginning at birth [Oe et al 2005]. The presence of type 1 EKG changes should be further investigated.

Agents/Circumstances to Avoid

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

• Febrile state
• Vagotonic agents
• Alpha-adrenergic agonists [Miyazaki et al 1996]
• Beta-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 Brugada syndrome-related pathogenic variant has been identified in an affected family member, molecular genetic testing of at-risk relatives (including children) is appropriate because:

• EKG changes have low sensitivity in establishing the diagnosis [Corcia 2022];
• Identification of individuals at risk allows preventive measures such as fever control and avoidance of medications that can induce ventricular arrhythmias;
• Cardiac surveillance can be limited to family members who have the familial Brugada syndrome-related pathogenic variant [Benito et al 2009, Escárcega et al 2009, Nunn et al 2010].

Individuals with a known pathogenic variant should undergo EKG monitoring every one to two years beginning at birth (see Surveillance).

If the pathogenic variant has not been identified in the family, relatives should undergo EKG monitoring every one to two years beginning at birth (see Surveillance). If a type I EKG is identified, further investigation is warranted.

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

Pregnancy Management

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

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

Therapies Under Investigation

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

Mode of Inheritance

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

Risk to Family Members (Autosomal Dominant Inheritance)

Parents of a proband

• Most individuals diagnosed with Brugada syndrome have an affected parent or another affected close relative.
• A proband with Brugada syndrome may have the disorder as the result of a de novo pathogenic variant. The proportion of individuals with Brugada syndrome caused by a de novo pathogenic variant is very low (~1%).
• If a diagnosis of Brugada syndrome has not already been established in the mother or the father of the proband, recommendations for the evaluation of parents of a proband include electrocardiographic analysis, attention to a family history of sudden death, and (if the pathogenic variant in the proband has been identified) molecular genetic testing.
• If the proband has a known pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• 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. Therefore, an apparently negative family history cannot be confirmed unless the proband has a known Brugada syndrome-related pathogenic variant that is not identified in either parent.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected, or unaffected but known to be heterozygous for the pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%.
  • The risk that a sib will inherit the familial pathogenic variant and develop Brugada syndrome may be less than 50% because of reduced penetrance and the possibility of other genetic and environmental factors (see Penetrance). Reduced penetrance and variable expressivity are hallmarks of Brugada syndrome.
  • Sibs who do not inherit the variant identified in the proband are at approximately the same risk for Brugada syndrome as the general population due to the possibility of other genetic variants.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs of inheriting the pathogenic variant is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents are clinically unaffected but their genetic status is unknown (because the parents have not undergone molecular genetic testing and/or a causative pathogenic variant has not been identified in the proband), sibs are still at increased risk for Brugada syndrome because of the possibility of reduced penetrance in a parent (i.e., a clinically unaffected parent may be heterozygous for a pathogenic variant) and the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant Brugada syndrome has a 50% chance of inheriting a Brugada syndrome-related pathogenic variant.

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

Family planning

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

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the Brugada syndrome-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for Brugada syndrome are possible.

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

Molecular Pathogenesis

SCN5A encodes the alpha subunit of the cardiac sodium channel and is responsible for the initial upstroke of the action potential in the EKG. This integral membrane protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na+ ions may pass in accordance with their electrochemical gradient. SCN5A is expressed in human atrial and ventricular cardiac muscle.

Mechanism of disease causation. Pathogenic variants in SCN5A result in decrease in Na⁺ current availability by affecting the structure, function, and trafficking of the sodium channel.

Author Notes

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

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

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

Acknowledgments

Research support is provided by CIBERCV and Fundació Obra Social La Caixa.

Revision History

• 25 August 2022 (sw) Comprehensive update posted live
• 17 November 2016 (ma) Comprehensive update posted live
• 10 April 2014 (me) Comprehensive update posted live
• 16 August 2012 (cd) Revision: multigene panels for Brugada syndrome and sudden cardiac death available clinically
• 12 January 2012 (cd) Revision: clinical testing for mutations in CACNB2 and HCN4 now listed in the GeneTests™ Laboratory Directory; large deletion in SCN5A reported [Eastaugh et al 2011]
• 8 September 2011 (me) Comprehensive update posted live
• 11 August 2009 (cd) Revision: prenatal testing for SCN5A available clinically
• 7 December 2007 (me) Comprehensive update posted live
• 31 March 2005 (me) Review posted live
• 11 March 2004 (rb) Original submission

Literature Cited

• Al-Khatib SM. Risk stratification of individuals with the Brugada electrocardiogram: a myth or a reality? J Cardiovasc Electrophysiol. 2006;17:584–5. [PubMed: 16836702]
• Antzelevitch C. Molecular biology and cellular mechanisms of Brugada and long QT syndromes in infants and young children. J Electrocardiol. 2001;34 Suppl:177–81. [PubMed: 11781953]
• Antzelevitch C, Brugada P, Brugada J, Brugada R, Shimizu W, Gussak I, Perez Riera AR. Brugada syndrome: a decade of progress. Circ Res. 2002;91:1114–8. [PubMed: 12480811]
• Antzelevitch C, Brugada P, Brugada J, Brugada R, Towbin JA, Nademanee K. Brugada syndrome: 1992-2002: a historical perspective. J Am Coll Cardiol. 2003;41:1665–71. [PubMed: 12767644]
• Becker F, Reid CA, Hallmann K, Tae HS, Phillips AM, Teodorescu G, Weber YG, Kleefuss-Lie A, Elger C, Perez-Reyes E, Petrou S, Kunz WS, Lerche H, Maljevic S. Functional variants in HCN4 and CACNA1H may contribute to genetic generalized epilepsy. Epilepsia Open. 2017;2:334–42. [PMC free article: PMC5862120] [PubMed: 29588962]
• Belhassen B, Glick A, Viskin S. Efficacy of quinidine in high-risk patients with Brugada syndrome. Circulation. 2004;110:1731–7. [PubMed: 15381640]
• Benito B, Brugada J. Recurrent syncope: an unusual presentation of Brugada syndrome. Nat Clin Pract Cardiovasc Med. 2006;3:573–7. [PubMed: 16990843]
• Benito B, Brugada J, Brugada R, Brugada P. Brugada syndrome. Rev Esp Cardiol. 2009;62:1297–315. [PubMed: 19889341]
• Benson DW, Wang DW, Dyment M, Knilans TK, Fish FA, Strieper MJ, Rhodes TH, George AL Jr. Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A). J Clin Invest. 2003;112:1019–28. [PMC free article: PMC198523] [PubMed: 14523039]
• Berne P, Brugada J. Brugada syndrome 2012. Circ J. 2012;76:1563–71. [PubMed: 22789973]
• Brugada J, Brugada P, Brugada R. The syndrome of right bundle branch block ST segment elevation in V1 to V3 and sudden death--the Brugada syndrome. Europace. 1999a;1:156–66. [PubMed: 11225790]
• Brugada J, Campuzano O, Arbelo E, Sarquella-Brugada G, Brugada R. Present status of Brugada syndrome: JACC state-of-the-art review. J Am Coll Cardiol. 2018;72:1046–59. [PubMed: 30139433]
• Brugada P, Brugada R, Brugada J, Geelen P. Use of the prophylactic implantable cardioverter defibrillator for patients with normal hearts. Am J Cardiol. 1999b;83:98D–100D. [PubMed: 10089849]
• Brugada R, Hong K, Dumaine R, Cordeiro J, Gaita F, Borggrefe M, Menendez TM, Brugada J, Pollevick GD, Wolpert C, Burashnikov E, Matsuo K, Wu YS, Guerchicoff A, Bianchi F, Giustetto C, Schimpf R, Brugada P, Antzelevitch C. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation. 2004;109:30–5. [PubMed: 14676148]
• Burashnikov E, Pfeiffer R, Barajas-Martinez H, Delpón E, Hu D, Desai M, Borggrefe M, Häissaguerre M, Kanter R, Pollevick GD, Guerchicoff A, Laiño R, Marieb M, Nademanee K, Nam GB, Robles R, Schimpf R, Stapleton DD, Viskin S, Winters S, Wolpert C, Zimmern S, Veltmann C, Antzelevitch C. Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. Heart Rhythm. 2010;7:1872–82. [PMC free article: PMC2999985] [PubMed: 20817017]
• Campostrini G, DiFrancesco JC, Castellotti B, Milanesi R, Gnecchi-Ruscone T, Bonzanni M, Bucchi A, Baruscotti M, Ferrarese C, Franceschetti S, Canafoglia L, Ragona F, Freri E, Labate A, Gambardella A, Costa C, Gellera C, Granata T, Barbuti A, DiFrancesco D. A loss-of-function HCN4 mutation associated with familial benign myoclonic epilepsy in infancy causes increased neuronal excitability. Front Mol Neurosci. 2018;11:269. [PMC free article: PMC6089338] [PubMed: 30127718]
• Chimparlee N, Prechawat S, Khongphatthanayothin A, Mauleekoonphairoj J, Lekchuensakul S, Wongcharoen W, Makarawate P, Sahasatas D, Krittayaphong R, Amnueypol M, Anannab A, Ngarmukos T, Vardhanabhuti S, Sutjaporn B, Wandee P, Veerakul G, Bezzina CR, Poovorawan Y, Nademanee K. Clinical characteristics of SCN5A p.R965C carriers: a common founder variant predisposing to Brugada syndrome in Thailand. Circ Genom Precis Med. 2021;14:e003229. [PubMed: 34092119]
• Ciconte G, Monasky MM, Santinelli V, Micaglio E, Vicedomini G, Anastasia L, Negro G, Borrelli V, Giannelli L, Santini F, de Innocentiis C, Rondine R, Locati ET, Bernardini A, Mazza BC, Mecarocci V, Ćalović Ž, Ghiroldi A, D'Imperio S, Benedetti S, Di Resta C, Rivolta I, Casari G, Petretto E, Pappone C. Brugada syndrome genetics is associated with phenotype severity. Eur Heart J. 2021;42:1082–90. [PMC free article: PMC7955973] [PubMed: 33221895]
• Corcia MCG. Brugada syndrome - minimizing overdiagnosis and over treatment in children. Curr Opin Cardiol. 2022;37:80–5. [PubMed: 34654031]
• Delise P, Marras E, Bocchino M. Brugada-like electrocardiogram pattern: how to stratify the risk for sudden cardiac death. Is sports activity contraindicated? J Cardiovasc Med (Hagerstown). 2006;7:239–45. [PubMed: 16645396]
• de Oliveira Neto NR, de Oliveira WS, Mastrocola F, Sacilotto L. Brugada phenocopy: Mechanisms, diagnosis, and implications. J Electrocardiol. 2019;55:45–50. [PubMed: 31078108]
• Eastaugh LJ, James PA, Phelan DG, Davis AM. Brugada syndrome caused by a large deletion in SCN5A only detected by multiplex ligation-dependent probe amplification. J Cardiovasc Electrophysiol. 2011;22:1073–6. [PubMed: 21288276]
• Eckardt L, Probst V, Smits JP, Bahr ES, Wolpert C, Schimpf R, Wichter T, Boisseau P, Heinecke A, Breithardt G, Borggrefe M, LeMarec H, Bocker D, Wilde AA. Long-term prognosis of individuals with right precordial ST-segment-elevation Brugada syndrome. Circulation. 2005;111:257–63. [PubMed: 15642768]
• Escárcega RO, Jiménez-Hernández M, Garcia-Carrasco M, Perez-Alva JC, Brugada J. The Brugada syndrome. Acta Cardiol. 2009;64:795–801. [PubMed: 20128157]
• Faber CG, Lauria G, Merkies IS, Cheng X, Han C, Ahn HS, Persson AK, Hoeijmakers JG, Gerrits MM, Pierro T, Lombardi R, Kapetis D, Dib-Hajj SD, Waxman SG. Gain-of-function Nav1.8 mutations in painful neuropathy. Proc Natl Acad Sci U S A. 2012;109:19444–9. [PMC free article: PMC3511073] [PubMed: 23115331]
• Francis J, Antzelevitch C. Brugada syndrome. Int J Cardiol. 2005;101:173–8. [PMC free article: PMC1474051] [PubMed: 15882659]
• Gehi AK, Duong TD, Metz LD, Gomes JA, Mehta D. Risk stratification of individuals with the Brugada electrocardiogram: a meta-analysis. J Cardiovasc Electrophysiol. 2006;17:577–83. [PubMed: 16836701]
• Glatter KA, Chiamvimonvat N, Viitasalo M, Wang Q, Tuteja D. Risk stratification in Brugada syndrome. Lancet. 2005;366:530–1. [PMC free article: PMC1579825] [PubMed: 16099276]
• Grunnet M, Diness TG, Hansen RS, Olesen SP. Biophysical characterization of the short QT mutation hERG-N588K reveals a mixed gain-and loss-of-function. Cell Physiol Biochem. 2008;22:611–24. [PubMed: 19088443]
• Hata Y, Chiba N, Hotta K, et al. Incidence and clinical significance of right bundle branch block and ST segment elevation in V1-V3 in 6-to 18-year-old school children in Japan. Circulation. 1997;20:2310.
• Hermida JS, Denjoy I, Clerc J, Extramiana F, Jarry G, Milliez P, Guicheney P, Di Fusco S, Rey JL, Cauchemez B, Leenhardt A. Hydroquinidine therapy in Brugada syndrome. J Am Coll Cardiol. 2004;43:1853–60. [PubMed: 15145111]
• Hong K, Berruezo-Sanchez A, Poungvarin N, Oliva A, Vatta M, Brugada J, Brugada P, Towbin JA, Dumaine R, Pinero-Galvez C, Antzelevitch C, Brugada R. Phenotypic characterization of a large European family with Brugada syndrome displaying a sudden unexpected death syndrome mutation in SCN5A. J Cardiovasc Electrophysiol. 2004a;15:64–9. [PubMed: 15028074]
• Hong K, Brugada J, Oliva A, Berruezo-Sanchez A, Potenza D, Pollevick GD, Guerchicoff A, Matsuo K, Burashnikov E, Dumaine R, Towbin JA, Nesterenko V, Brugada P, Antzelevitch C, Brugada R. Value of electrocardiographic parameters and ajmaline test in the diagnosis of Brugada syndrome caused by SCN5A mutations. Circulation. 2004b;110:3023–7. [PMC free article: PMC1513622] [PubMed: 15520322]
• Hu D, Barajas-Martínez H, Terzic A, Park S, Pfeiffer R, Burashnikov E, Wu Y, Borggrefe M, Veltmann C, Schimpf R, Cai JJ, Nam GB, Deshmukh P, Scheinman M, Preminger M, Steinberg J, López-Izquierdo A, Ponce-Balbuena D, Wolpert C, Haïssaguerre M, Sánchez-Chapula JA, Antzelevitch C. ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene. Int J Cardiol. 2014;171:431–42. [PMC free article: PMC3947869] [PubMed: 24439875]
• Huang MH, Marcus FI. Idiopathic Brugada-type electrocardiographic pattern in an octogenarian. J Electrocardiol. 2004;37:109–11. [PubMed: 15127377]
• Ikeda T, Takami M, Sugi K, Mizusawa Y, Sakurada H, Yoshino H. Noninvasive risk stratification of subjects with a Brugada-type electrocardiogram and no history of cardiac arrest. Ann Noninvasive Electrocardiol. 2005;10:396–403. [PMC free article: PMC6932722] [PubMed: 16255748]
• Imaki R, Niwano S, Fukaya H, Sasaki S, Yuge M, Hirasawa S, Sato D, Sasaki T, Moriguchi M, Izumi T. Predictive impact of the inducibility of ventricular fibrillation in patients with Brugada-type ECG. Int Heart J. 2006;47:229–36. [PubMed: 16607050]
• Ito H, Yano K, Chen R, He Q, Curb JD. The prevalence and prognosis of a Brugada-type electrocardiogram in a population of middle-aged Japanese-American men with follow-up of three decades. Am J Med Sci. 2006;331:25–9. [PubMed: 16415660]
• Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, Brugada P, Fressart V, Guerchicoff A, Harris-Kerr C, Kamakura S, Kyndt F, Koopmann TT, Miyamoto Y, Pfeiffer R, Pollevick GD, Probst V, Zumhagen S, Vatta M, Towbin JA, Shimizu W, Schulze-Bahr E, Antzelevitch C, Salisbury BA, Guicheney P, Wilde AA, Brugada R, Schott JJ, Ackerman MJ. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm. 2010;7:33–46. [PMC free article: PMC2822446] [PubMed: 20129283]
• Karaca M, Dinckal MH. Monomorphic and propafenone-induced polymorphic ventricular tachycardia in Brugada syndrome: a case report. Acta Cardiol. 2006;61:481–4. [PubMed: 16970061]
• Kruse M, Schulze-Bahr E, Corfield V, Beckmann A, Stallmeyer B, Kurtbay G, Ohmert I, Schulze-Bahr E, Brink P, Pongs O. Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I. J Clin Invest. 2009;119:2737–44. [PMC free article: PMC2735920] [PubMed: 19726882]
• Lizotte E, Junttila MJ, Dube MP, Hong K, Benito B, De Zutter M, Henkens S, Sarkozy A, Huikuri HV, Towbin J, Vatta M, Brugada P, Brugada J, Brugada R. Genetic modulation of brugada syndrome by a common polymorphism. J Cardiovasc Electrophysiol. 2009;20:1137–41. [PubMed: 19549036]
• Makiyama T, Akao M, Tsuji K, Doi T, Ohno S, Takenaka K, Kobori A, Ninomiya T, Yoshida H, Takano M, Makita N, Yanagisawa F, Higashi Y, Takeyama Y, Kita T, Horie M. High risk for bradyarrhythmic complications in patients with Brugada syndrome caused by SCN5A gene mutations. J Am Coll Cardiol. 2005;46:2100–6. [PubMed: 16325048]
• Mates J, Mademont-Soler I, Fernandez-Falgueras A, Sarquella-Brugada G, Cesar S, Arbelo E, García-Álvarez A, Jordà P, Toro R, Coll M, Fiol V, Iglesias A, Perez-Serra A, Olmo BD, Alcalde M, Puigmulé M, Pico F, Lopez L, Ferrer C, Tiron C, Grassi S, Oliva A, Brugada J, Brugada R, Campuzano O. Sudden cardiac death and copy number variants: what do we know after 10 years of genetic analysis? Forensic Sci Int Genet. 2020;47:102281. [PubMed: 32248082]
• Maury P, Couderc P, Delay M, Boveda S, Brugada J. Electrical storm in Brugada syndrome successfully treated using isoprenaline. Europace. 2004;6:130–3. [PubMed: 15018871]
• Meregalli PG, Tan HL, Probst V, Koopmann TT, Tanck MW, Bhuiyan ZA, Sacher F, Kyndt F, Schott JJ, Albuisson J, Mabo P, Bezzina CR, Le Marec H, Wilde AA. Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies. Heart Rhythm. 2009;6:341–8. [PubMed: 19251209]
• Mills AT, Dasan S, Wan A. Brugada syndrome: syncope in the younger patient and the risk of sudden cardiac death. Emerg Med J. 2005;22:604–6. [PMC free article: PMC1726898] [PubMed: 16046779]
• Miyazaki T, Mitamura H, Miyoshi S, Soejima K, Aizawa Y, Ogawa S. Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome. J Am Coll Cardiol. 1996;27:1061–70. [PubMed: 8609322]
• Morita H, Kusano KF, Miura D, Nagase S, Nakamura K, Morita ST, Ohe T, Zipes DP, Wu J. Fragmented QRS as a marker of conduction abnormality and a predictor of prognosis of Brugada syndrome. Circulation. 2008;118:1697–704. [PubMed: 18838563]
• Morita H, Zipes DP, Wu J. Brugada syndrome: insights of ST elevation, arrhythmogenicity, and risk stratification from experimental observations. Heart Rhythm. 2009;6:S34–43. [PubMed: 19880072]
• Nakazato Y, Suzuki T, Yasuda M, Daida H. Manifestation of Brugada syndrome after pacemaker implantation in a patient with sick sinus syndrome. J Cardiovasc Electrophysiol. 2004;15:1328–30. [PubMed: 15574187]
• Namiki T, Ogura T, Kuwabara Y, et al. Five-year mortality and clinical characteristics of adult subjects with right bundle branch block and ST elevation. Circulation. 1995;93:334.
• Nunn L, Bhar-Amato J, Lambiase P. Brugada syndrome: controversies in risk stratification and management. Indian Pacing Electrophysiol J. 2010;10:400–9. [PMC free article: PMC2933368] [PubMed: 20930958]
• Oe H, Takagi M, Tanaka A, Namba M, Nishibori Y, Nishida Y, Kawarabayashi T, Yoshiyama M, Nishimoto M, Tanaka K, Yoshikawa J. Prevalence and clinical course of the juveniles with Brugada-type ECG in Japanese population. Pacing Clin Electrophysiol. 2005;28:549–54. [PubMed: 15955188]
• Ohno S, Zankov DP, Ding WG, Itoh H, Makiyama T, Doi T, Shizuta S, Hattori T, Miyamoto A, Naiki N, Hancox JC, Matsuura H, Horie M. KCNE5 (KCNE1L) variants are novel modulators of Brugada syndrome and idiopathic ventricular fibrillation. Circ Arrhythm Electrophysiol. 2011;4:352–61. [PubMed: 21493962]
• Olson TM, Alekseev AE, Moreau C, Liu XK, Zingman LV, Miki T, Seino S, Asirvatham SJ, Jahangir A, Terzic A. KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation. Nat Clin Pract Cardiovasc Med. 2007;4:110–6. [PMC free article: PMC2013306] [PubMed: 17245405]
• Olson TM, Michels VV, Ballew JD, Reyna SP, Karst ML, Herron KJ, Horton SC, Rodeheffer RJ, Anderson JL. Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. JAMA. 2005;293:447–54. [PMC free article: PMC2039897] [PubMed: 15671429]
• Ott P, Marcus F. The Brugada syndrome: can we predict the risk? J Cardiovasc Electrophysiol. 2006;17:608–9. [PubMed: 16836707]
• Perrin MJ, Adler A, Green S, Al-Zoughool F, Doroshenko P, Orr N, Uppal S, Healey JS, Birnie D, Sanatani S, Gardner M, Champagne J, Simpson C, Ahmad K, van den Berg MP, Chauhan V, Backx PH, van Tintelen JP, Krahn AD, Gollob MH. Evaluation of genes encoding for the transient outward current (Ito) identifies the KCND2 gene as a cause of J-wave syndrome associated with sudden cardiac death. Circ Cardiovasc Genet. 2014;7:782–9. [PubMed: 25214526]
• Poelzing S, Forleo C, Samodell M, Dudash L, Sorrentino S, Anaclerio M, Troccoli R, Iacoviello M, Romito R, Guida P, Chahine M, Pitzalis M, Deschênes I. SCN5A polymorphism restores trafficking of a Brugada syndrome mutation on a separate gene. Circulation. 2006;114:368–76. [PubMed: 16864729]
• Priori SG, Napolitano C, Giordano U, Collisani G, Memmi M. Brugada syndrome and sudden cardiac death in children. Lancet. 2000;355:808–9. [PubMed: 10711933]
• Probst V, Evain S, Gournay V, Marie A, Schott JJ, Boisseau P, LE, Marec H. Monomorphic ventricular tachycardia due to Brugada syndrome successfully treated by hydroquinidine therapy in a 3-year-old child. J Cardiovasc Electrophysiol. 2006;17:97–100. [PubMed: 16426410]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Ramadan W, Patel N, Anazi S, Kentab AY, Bashiri FA, Hamad MH, Jad L, Salih MA, Alsaif H, Hashem M, Faqeih E, Shamseddin HE, Alkuraya FS. Confirming the recessive inheritance of SCN1B mutations in developmental epileptic encephalopathy. Clin Genet. 2017;92:327–31. [PubMed: 28218389]
• Ravn LS, Aizawa Y, Pollevick GD, Hofman-Bang J, Cordeiro JM, Dixen U, Jensen G, Wu Y, Burashnikov E, Haunso S, Guerchicoff A, Hu D, Svendsen JH, Christiansen M, Antzelevitch C. Gain of function in IKs secondary to a mutation in KCNE5 associated with atrial fibrillation. Heart Rhythm. 2008;5:427–35. [PMC free article: PMC2515863] [PubMed: 18313602]
• Rodríguez-Mañero M, Baluja A, Hernández J, Muñoz C, Calvo D, Fernández-Armenta J, García-Fernández A, Zorio E, Arce-León Á, Sánchez-Gómez JM, Mosquera-Pérez I, Arias MÁ, Díaz-Infante E, Expósito V, Jiménez-Ramos V, Teijeira E, Cañadas-Godoy MV, Guerra-Ramos JM, Oloriz T, Basterra N, Sousa P, Elices-Teja J, García-Bolao I, González-Juanatey JR, Brugada R, Gimeno JR, Brugada J, Arbelo E. Validation of multiparametric approaches for the prediction of sudden cardiac death in patients with Brugada syndrome and electrophysiological study. Rev Esp Cardiol (Engl Ed). 2022;75:559–67. [PubMed: 34479845]
• Scheffer IE, Harkin LA, Grinton BE, Dibbens LM, Turner SJ, Zielinski MA, Xu R, Jackson G, Adams J, Connellan M, Petrou S, Wellard RM, Briellmann RS, Wallace RH, Mulley JC, Berkovic SF. Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations. Brain. 2007;130:100–9. [PubMed: 17020904]
• Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, Wilde AA, Escande D, Mannens MM, Le Marec H. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet. 1999;23:20–1. [PubMed: 10471492]
• Sharif-Kazemi MB, Emkanjoo Z, Tavoosi A, Kafi M, Kheirkhah J, Alizadeh A, Sadr-Ameli MA. Electrical storm in Brugada syndrome during pregnancy. Pacing Clin Electrophysiol. 2011;34:e18–21. [PubMed: 20353417]
• Siekierska A, Isrie M, Liu Y, Scheldeman C, Vanthillo N, Lagae L, de Witte PA, Van Esch H, Goldfarb M, Buyse GM. Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy. Neurology. 2016;86:2162–70. [PMC free article: PMC4898311] [PubMed: 27164707]
• Singh B, Ogiwara I, Kaneda M, Tokonami N, Mazaki E, Baba K, Matsuda K, Inoue Y, Yamakawa K. A. Kv4.2 truncation mutation in a patient with temporal lobe epilepsy. Neurobiol Dis. 2006;24:245–53. [PubMed: 16934482]
• Skinner JR, Chung SK, Montgomery D, McCulley CH, Crawford J, French J, Rees MI. Near-miss SIDS due to Brugada syndrome. Arch Dis Child. 2005;90:528–9. [PMC free article: PMC1720395] [PubMed: 15851440]
• Smits JP, Eckardt L, Probst V, Bezzina CR, Schott JJ, Remme CA, Haverkamp W, Breithardt G, Escande D, Schulze-Bahr E, LeMarec H, Wilde AA. Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients. J Am Coll Cardiol. 2002;40:350–6. [PubMed: 12106943]
• Smits JP, Koopmann TT, Wilders R, Veldkamp MW, Opthof T, Bhuiyan ZA, Mannens MM, Balser JR, Tan HL, Bezzina CR, Wilde AA. A mutation in the human cardiac sodium channel (E161K) contributes to sick sinus syndrome, conduction disease and Brugada syndrome in two families. J Mol Cell Cardiol. 2005;38:969–81. [PubMed: 15910881]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD^®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Tan HL, Bink-Boelkens MT, Bezzina CR, Viswanathan PC, Beaufort-Krol GC, van Tintelen PJ, van den Berg MP, Wilde AA, Balser JR. A sodium-channel mutation causes isolated cardiac conduction disease. Nature. 2001;409:1043–7. [PubMed: 11234013]
• Tatsumi H, Takagi M, Nakagawa E, Yamashita H, Yoshiyama M. Risk stratification in patients with Brugada syndrome: analysis of daily fluctuations in 12-lead electrocardiogram (ECG) and signal-averaged electrocardiogram (SAECG). J Cardiovasc Electrophysiol. 2006;17:705–11. [PubMed: 16836663]
• Templin C, Ghadri JR, Rougier JS, Baumer A, Kaplan V, Albesa M, Sticht H, Rauch A, Puleo C, Hu D, Barajas-Martinez H, Antzelevitch C, Lüscher TF, Abriel H, Duru F. Identification of a novel loss-of-function calcium channel gene mutation in short QT syndrome (SQTS6). Eur Heart J. 2011;32:1077–88. [PMC free article: PMC3086900] [PubMed: 21383000]
• Tohyou Y, Nakazawa K, Ozawa A, Tanaka O, Watanuki M, Takagi A, Akagi T, Masui Y, Matumoto N, Miyake F, Murayama M. A survey in the incidence of right bundle branch block with ST segment elevation among normal population. Jpn J Electrocardiol. 1995;15:223–6.
• Van Norstrand DW, Valdivia CR, Tester DJ, Ueda K, London B, Makielski JC, Ackerman MJ. Molecular and functional characterization of novel glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) mutations in sudden infant death syndrome. Circulation. 2007;116:2253–9. [PMC free article: PMC3332545] [PubMed: 17967976]
• Vatta M, Dumaine R, Varghese G, Richard TA, Shimizu W, Aihara N, Nademanee K, Brugada R, Brugada J, Veerakul G, Li H, Bowles NE, Brugada P, Antzelevitch C, Towbin JA. Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome. Hum Mol Genet. 2002;11:337–45. [PubMed: 11823453]
• Viswanathan PC, Benson DW, Balser JR. A common SCN5A polymorphism modulates the biophysical effects of an SCN5A mutation. J Clin Invest. 2003;111:341–6. [PMC free article: PMC151865] [PubMed: 12569159]
• Wang DW, Viswanathan PC, Balser JR, George AL Jr, Benson DW. Clinical, genetic, and biophysical characterization of SCN5A mutations associated with atrioventricular conduction block. Circulation. 2002;105:341–6. [PubMed: 11804990]
• Wang H, Xu Z, Lee BH, Vu S, Hu L, Lee M, Bu D, Cao X, Hwang S, Yang Y, Zheng J, Lin Z. Gain-of-function mutations in TRPM4 activation gate cause progressive symmetric erythrokeratodermia. J Invest Dermatol. 2019;139:1089–97. [PubMed: 30528822]
• Wang P, Yang Q, Wu X, Yang Y, Shi L, Wang C, Wu G, Xia Y, Yang B, Zhang R, Xu C, Cheng X, Li S, Zhao Y, Fu F, Liao Y, Fang F, Chen Q, Tu X, Wang QK. Functional dominant-negative mutation of sodium channel subunit gene SCN3B associated with atrial fibrillation in a Chinese GeneID population. Biochem Biophys Res Commun. 2010;398:98–104. [PMC free article: PMC3132081] [PubMed: 20558140]
• Watanabe H, Darbar D, Kaiser DW, Jiramongkolchai K, Chopra S, Donahue BS, Kannankeril PJ, Roden DM. Mutations in sodium channel β1- and β2-subunits associated with atrial fibrillation. Circ Arrhythm Electrophysiol. 2009;2:268–75. [PMC free article: PMC2727725] [PubMed: 19808477]
• Watanabe H, Nogami A, Ohkubo K, Kawata H, Hayashi Y, Ishikawa T, Makiyama T, Nagao S, Yagihara N, Takehara N, Kawamura Y, Sato A, Okamura K, Hosaka Y, Sato M, Fukae S, Chinushi M, Oda H, Okabe M, Kimura A, Maemura K, Watanabe I, Kamakura S, Horie M, Aizawa Y, Shimizu W, Makita N. Electrocardiographic characteristics and SCN5A mutations in idiopathic ventricular fibrillation associated with early repolarization. Circ Arrhythm Electrophysiol. 2011;4:874–81. [PubMed: 22028457]
• Weese-Mayer DE, Ackerman MJ, Marazita ML, Berry-Kravis EM. Sudden infant death syndrome: review of implicated genetic factors. Am J Med Genet A. 2007;143A:771–88. [PubMed: 17340630]
• Wilde AA, Antzelevitch C, Borggrefe M, Brugada J, Brugada R, Brugada P, Corrado D, Hauer RN, Kass RS, Nademanee K, Priori SG, Towbin JA. Proposed diagnostic criteria for the Brugada syndrome: consensus report. Circulation. 2002;106:2514–9. [PubMed: 12417552]
• Wilde AAM, Semsarian C, Márquez MF, Sepehri Shamloo A, Ackerman MJ, Ashley EA, Sternick EB, Barajas-Martinez H, Behr ER, Bezzina CR, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob MH, Lubitz S, Makita N, Ohno S, Ortiz-Genga M, Sacilotto L, Schulze-Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware JS, Winlaw DS, Kaufman ES, et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. Europace. 2022. Epub ahead of print. [PubMed: 35390533]
• Yang Y, Xia M, Jin Q, Bendahhou S, Shi J, Chen Y, Liang B, Lin J, Liu Y, Liu B, Zhou Q, Zhang D, Wang R, Ma N, Su X, Niu K, Pei Y, Xu W, Chen Z, Wan H, Cui J, Barhanin J, Chen Y. Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation. Am J Hum Genet. 2004;75:899–905. [PMC free article: PMC1182120] [PubMed: 15368194]
• Yokokawa M, Noda T, Okamura H, Satomi K, Suyama K, Kurita T, Aihara N, Kamakura S, Shimizu W. Comparison of long-term follow-up of electrocardiographic features in Brugada syndrome between the SCN5A-positive probands and the SCN5A-negative probands. Am J Cardiol. 2007;100:649–55. [PubMed: 17697823]