Present Status of Brugada Syndrome

Brugada, Josép; Campuzano, Òscar; Arbelo, Elena; Sarquella‐Brugada, Georgia; Brugada, Ramón

doi:10.1016/j.jacc.2018.06.037

Cited by 346 publications

(294 citation statements)

References 102 publications

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“…Syncope is an indisputable predictor of risk, and 17% to 62% of BrS patients are likely to suffer from an MAE during follow up. 4 Our pooled analysis indicated that the proportion of syncope (37% vs 31%; P = .31; Figure S3) and ACA (21% vs 18%; P = .79; Figure S3) did not significantly differ between the SCN5A(+) and SCN5A(−) patients ( Table 2).…”

Section: History Of Syncope or Acamentioning

confidence: 84%

“…Mutations in the SCN5A gene, which encodes the alpha subunit of voltage‐gated sodium channel type 5 (Nav1.5), are linked to a wide spectrum of inherited conditions including type‐3 long QT syndrome (LQT3), Brugada syndrome (BrS), progressive cardiac conduction defect, familial atrial fibrillation (AF), and dilated cardiomyopathy . Thereinto, BrS is a rare heritable arrhythmia syndrome which is characterized by a coved‐type ST‐segment elevation in the right precordial leads on electrocardiogram (ECG), it has been suggested that Brugada syndrome increased the risk of sudden cardiac death (SCD) . Most BrS patients are males, who have a higher risk of arrhythmic events than females .…”

Section: Introductionmentioning

confidence: 99%

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Brugada syndrome with SCN5A mutations exhibits more pronounced electrophysiological defects and more severe prognosis: A meta‐analysis

et al. 2019

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Whether the presence of SCN5A mutation is a predictor of BrS risk remains controversial, and patient selection bias may have weakened previous findings. Therefore, we performed this study to clarify the clinical characteristics and outcomes of BrS probands with SCN5A mutations. We systematically retrieved eligible studies published through October 2018. A total of 17 studies enrolling 1780 BrS patients were included. Overall, our results found that compared with BrS patients without SCN5A mutations, patients with SCN5A mutations exhibited a younger age at the onset of symptoms and higher rate of the spontaneous type-1 electrocardiogram pattern, more pronounced conduction or repolarization abnormalities, and increased atrial vulnerability. In addition, the presence of SCN5A mutations was associated with an elevated risk of major arrhythmic events in both Asian (odds ratio [OR] = 1.82, 95% confidence interval [CI] 1.07-3.11; P = .03) and Caucasian (OR = 2.24, 95% CI 1.02-4.90; P = .04) populations. In conclusions, patients with SCN5A mutations exhibit more pronounced electrophysiological defects and more severe prognosis.Clinicians should be cautious when utilizing genetic testing for risk stratification or treatment guidance before determining whether the causal relationship regarding SCN5A mutation status is an independent predictor of risk.

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Section: History Of Syncope or Acamentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Brugada syndrome with SCN5A mutations exhibits more pronounced electrophysiological defects and more severe prognosis: A meta‐analysis

et al. 2019

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“…Given the uncertain significance of many variants found in BrS patients, including the variability between people with the same variant and the lack of functional studies in most cases, recent studies have focused on understanding the phenotypic effect of individual variants within the SCN5A gene [16,19,28,42,43,77,79,80], as well as the search for additional genes involved in this multi-causative pathology [32,77,[81][82][83]. As previously mentioned, one such study demonstrated the similarity in phenotype between patients harboring SCN10A variants, as opposed to SCN5A variants, including personal history of cardiac arrest/syncope, spontaneous BrS electrocardiogram pattern, family history of sudden death, and arrhythmic substrate [77].…”

Section: Sodium Channel Mutationsmentioning

confidence: 99%

Brugada Syndrome: Oligogenic or Mendelian Disease?

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Micaglio

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et al. 2020

IJMS

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Brugada syndrome (BrS) is diagnosed by a coved-type ST-segment elevation in the right precordial leads on the electrocardiogram (ECG), and it is associated with an increased risk of sudden cardiac death (SCD) compared to the general population. Although BrS is considered a genetic disease, its molecular mechanism remains elusive in about 70-85% of clinically-confirmed cases. Variants occurring in at least 26 different genes have been previously considered causative, although the causative effect of all but the SCN5A gene has been recently challenged, due to the lack of systematic, evidence-based evaluations, such as a variant's frequency among the general population, family segregation analyses, and functional studies. Also, variants within a particular gene can be associated with an array of different phenotypes, even within the same family, preventing a clear genotype-phenotype correlation. Moreover, an emerging concept is that a single mutation may not be enough to cause the BrS phenotype, due to the increasing number of common variants now thought to be clinically relevant. Thus, not only the complete list of genes causative of the BrS phenotype remains to be determined, but also the interplay between rare and common multiple variants. This is particularly true for some common polymorphisms whose roles have been recently re-evaluated by outstanding works, including considering for the first time ever a polygenic risk score derived from the heterozygous state for both common and rare variants. The more common a certain variant is, the less impact this variant might have on heart function. We are aware that further studies are warranted to validate a polygenic risk score, because there is no mutated gene that connects all, or even a majority, of BrS cases. For the same reason, it is currently impossible to create animal and cell line genetic models that represent all BrS cases, which would enable the expansion of studies of this syndrome. Thus, the best model at this point is the human patient population. Further studies should first aim to uncover genetic variants within individuals, as well as to collect family segregation data to identify potential genetic causes of BrS.

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“…One current challenge is early identification of at-risk individuals, as the first expression of the disease is often SCD (Brugada et al, 2018 Note. The main gene is SCN5A, responsible for 25-30% of all cases.…”

Section: Discussionmentioning

confidence: 99%

“…the fourth decade of life (Brugada, Campuzano, Arbelo, Sarquella-Brugada, & Brugada, 2018). The prevalence of BrS ranges from 1/5,000 to 1/2,000, with significant ethnic, geographic, and gender differences (Quan et al, 2016).…”

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confidence: 99%

Genetic interpretation and clinical translation of minor genes related to Brugada syndrome

et al. 2019

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Brugada syndrome (BrS) is an inherited arrhythmogenic disease associated with sudden cardiac death. The main gene is SCN5A. Additional variants in 42 other genes have been reported as deleterious, although these variants have not yet received comprehensive pathogenic analysis. Our aim was to clarify the role of all currently reported variants in minor genes associated with BrS. We performed a comprehensive analysis according to the American College of Medical Genetics and Genomics guidelines of published clinical and basic data on all genes (other than SCN5A) related to BrS. Our results identified 133 rare variants potentially associated with BrS. After applying current recommendations, only six variants (4.51%) show a conclusive pathogenic role. All definitively pathogenic variants were located in four genes encoding sodium channels or related proteins: SLMAP, SEMA3A, SCNN1A, and SCN2B. In total, 33.83% of variants in 19 additional genes were potentially pathogenic. Beyond SCN5A, we conclude definitive pathogenic variants associated with BrS in four minor genes. The current list of genes associated with BrS, therefore, should include SCN5A, SLMAP, SEMA3A, SCNN1A, and SCN2B. Comprehensive genetic interpretation and careful clinical translation should be done for all variants currently classified as potentially deleterious for BrS.

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Present Status of Brugada Syndrome

Cited by 346 publications

References 102 publications

Brugada syndrome with SCN5A mutations exhibits more pronounced electrophysiological defects and more severe prognosis: A meta‐analysis

Brugada syndrome with SCN5A mutations exhibits more pronounced electrophysiological defects and more severe prognosis: A meta‐analysis

Brugada Syndrome: Oligogenic or Mendelian Disease?

Genetic interpretation and clinical translation of minor genes related to Brugada syndrome

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