An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing

Kapplinger, Jamie D.; Tester, David J.; Alders, Mariëlle; Benito, Begoña; Berthet, Myriam; Brugada, Josép; Brugada, Pedro; Fressart, Véronique; Guerchicoff, Alejandra; Harris‐Kerr, Carole; Kamakura, Shiro; Kyndt, Florence; Koopmann, Tamara T.; Miyamoto, Yoshihiro; Pfeiffer, Ryan; Pollevick, Guido D.; Probst, Vincent; Zumhagen, Sven; Vatta, Matteo; Towbin, Jeffrey A.; Shimizu, Wataru; Schulze‐Bahr, Eric; Antzelevitch, Charles; Salisbury, Benjamin A.; Guicheney, Pascale; Wilde, Arthur A.M.; Brugada, Ramón; Schott, Jean‐Jacques; Ackerman, Michael J.

doi:10.1016/j.hrthm.2009.09.069

Cited by 643 publications

(568 citation statements)

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“…In particular we found a 47% prevalence of SCN5A mutations in index patients, more than double that seen in adults with BrS 20 . Given the important role of conduction defects and increasing age in the pathophysiology of the disease 21,22 , one can speculate that the impairment of conduction associated with SCN5A mutations facilitates the development of BrS in the pediatric population.…”

Section: Scn5a Mutation Status and Its Implicationsmentioning

confidence: 45%

Impact of clinical and genetic findings on the management of young patients with Brugada syndrome

et al. 2016

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Section: Scn5a Mutation Status and Its Implicationsmentioning

confidence: 45%

Impact of clinical and genetic findings on the management of young patients with Brugada syndrome

et al. 2016

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“…Despite these ongoing developments in understanding the genetic causes of BrS, only 30-35% of clinically diagnosed cases are genetically diagnosed, and most of these (25-30%) result from pathogenic alterations in SCN5A. 53 SCN5A is responsible for phase 0 of the cardiac action potential, and pathogenic variations result in the inability of the sodium channel to function properly. The remaining BrS cases are attributable to alterations in one of the other known BrS-associated genes.…”

Section: Genetic Basismentioning

confidence: 99%

Brugada syndrome: clinical and genetic findings

Sarquella-Brugada

Campuzano

Arbelo

et al. 2016

Genetics in Medicine

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Review ARticleMore than 20 years ago, eight individuals were resuscitated from sudden cardiac death (SCD) caused by documented ventricular fibrillation (VF); all showed a characteristic ST segment elevation in the right precordial leads and a structurally normal heart. 1 In 1996, the term "Brugada syndrome" (BrS) was used to describe what was previously known as "right bundle branch block, persistent ST segment elevation, and sudden death syndrome. " 2 A year later, BrS was reported to be the same disease as sudden unexplained nocturnal death syndrome (SUNDS). In other countries, BrS has different names: Lai Tai (Thailand), Pokkuri (Japan), and Bangungut (Philippines). Currently, the prevalence of BrS is estimated at ~3-5 in 10,000 people, and it is higher in young men of Southeast Asian origin. It is the main cause of death among young healthy men in Southeast Asia. 3 Recent reports suggest that BrS could be responsible for 4% of all SCD and up to 12% of sudden death in patients with structurally normal hearts. The clinical phenotype manifests in adulthood, at a mean age of 41 years, and it is 8-to 10-times more frequent in males. Frequently, sudden death can be the first manifestation of the disease. 4 In 1998, the genetic basis of BrS was established when the sodium channel protein type V subunit α gene (SCN5A), which encodes the α-subunit of the voltage-gated Na v 1.5 cardiac sodium channel responsible for regulating rapid sodium current (I Na ), was associated with the disease. 5 Currently, BrS is recognized as a rare, inherited cardiac channelopathy caused by an alteration of ionic currents that leads to ventricular arrhythmias and SCD. It is clinically characterized by ST segment elevation in leads V1-V3 of the electrocardiogram, but incomplete penetrance and variable expressivity confound the diagnosis. 6 Despite the identification of 18 associated genes, 65-70% of clinically diagnosed cases remain without an identifiable genetic cause. 4 CLINICAL DIAGNOSIS Diagnostic criteriaThe clinical diagnosis of BrS requires the identification of the ST segment elevation in the right precordial leads at baseline or after the use of sodium blockers. Three different electrocardiographic (ECG) patterns can be often observed in families with BrS: type I, which consists of a coved-type ST segment elevation greater than 2 mm followed by a descending negative T wave in at least two right precordial leads (V1 to V3); type II ST elevation, saddleback-shaped patterns with a high initial increase followed by an ST elevation greater than 2 mm; and saddleback-shaped patterns with a high initial increase followed by an ST elevation less than 2 mm (Figure 1). The second Brugada Consensus Report proposed that only type I is diagnostic for BrS 7 and, in 2013, it was proposed that a definitive diagnosis of BrS considers both spontaneous type I pattern and a provoked type I pattern (with a baseline type II or III pattern) in at least one right precordial lead (V1 or V2). 8 The diagnosis of BrS is currently accepted in those patients ...

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“…There are 4 known common polymorphisms of the SCN5A gene related to BrS, including R34C, H558R, S1103Y, and R1193Q 7, 8. These SCN5A polymorphisms could decrease expression of sodium‐channel proteins and alter gating properties resulting in prolongation of the QRS duration and slow conduction in the heart 7, 9.…”

Section: Introductionmentioning

confidence: 99%

“…The SCN5A mutations may be associated with early and frequent VF recurrence or SCA in BrS patients, which may be related to fibrosis in the right ventricular outflow tract epicardial surface 10, 11. Most studies on SCN5A mutations included both asymptomatic and symptomatic BrS patients 8, 9, 10, 11. This study was aimed to investigate the association of SCN5A mutations and appropriate ICD shock therapy in only symptomatic BrS patients.…”

Section: Introductionmentioning

confidence: 99%

SCN5AGenetic Polymorphisms Associated With Increased Defibrillator Shocks in Brugada Syndrome

Makarawate

Chaosuwannakit

Vannaprasaht

et al. 2017

JAHA

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BackgroundBrugada syndrome (BrS) is an inherited primary arrhythmia disorder leading to sudden cardiac arrest. SCN5A, encoding the α‐subunit of the cardiac sodium channel (Nav1.5), is the most common pathogenic gene of BrS. An implantable cardioverter defibrillator (ICD) is the standard treatment for secondary prevention. This study aimed to evaluate association of the SCN5A variant with this cardiac conduction disturbance and appropriate ICD shock therapy in Thai symptomatic BrS patients with ICD implants.Methods and ResultsSymptomatic BrS patients diagnosed at university hospital were enrolled from 2008 to 2011. The primary outcome of the study was an appropriate ICD shock defined as having non‐pacing‐associated ICD shock after the occurrence of ventricular tachycardia or ventricular fibrillation. Associations between SCN5A polymorphisms, cardiac conduction disturbance, and potential confounding factors associated with appropriate ICD shock therapy were analyzed. All 40 symptomatic BrS patients (median age, 43 years) with ICD implantations were followed for 24 months. There were 16 patients (40%) who had the appropriate ICD shock therapy after ICD treatment. An independent factor associated with appropriate ICD shock therapy was SCN5A‐R1193Q with an adjusted hazard ratio of 10.550 (95% CI, 1.631–68.232).Conclusions SCN5A‐R1193Q is associated with cardiac conduction disturbances. It may be a genetic marker associated with ventricular arrhythmia leading to appropriate ICD shock therapy in symptomatic BrS patients with ICD treatment. Because of the small sample size of study population and the appropriate ICD shock outcome, further large studies are needed to confirm the results of this study.

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An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing

Abstract: BACKGROUND-Brugada syndrome (BrS) is a common heritable channelopathy. Mutations in the SCN5A-encoded sodium channel (BrS1) culminate in the most common genotype.

Cited by 643 publications

References 40 publications

Impact of clinical and genetic findings on the management of young patients with Brugada syndrome

Impact of clinical and genetic findings on the management of young patients with Brugada syndrome

Brugada syndrome: clinical and genetic findings

SCN5AGenetic Polymorphisms Associated With Increased Defibrillator Shocks in Brugada Syndrome

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