Dataset Information

Genetics of Brugada syndrome.

ABSTRACT: In 1992, the Brugada syndrome (BrS) was recognized as a disease responsible for sudden cardiac death, characterized by a right bundle-branch block with ST segment elevation in the leads V1 and V2. This syndrome is highly associated with sudden cardiac death, especially in young males. BrS is currently diagnosed in patients with ST-segment elevation showing type 1 morphology ? 2 mm in ?1 leads among the right precordial leads V1 or V2 positioned in the 2nd, 3rd, or 4th intercostal space, and occurring either spontaneously or after a provocative drug test by the intravenous administration of Class I antiarrhythmic drugs. With accumulated findings, the BrS inheritance model is believed to be an autosomal dominant inheritable model with incomplete penetrance, although most patients with BrS were sporadic cases. SCN5A, which was identified as the first BrS-associated gene in 1998, has emerged as the most common gene associated with BrS, and more than 10 BrS-associated genes have been identified thereafter. Mutation-specific genetic testing is recommended for the family members and appropriate relatives following the identification of BrS-causative mutations in an index patient. In addition, comprehensive or BrS1 (SCN5A) targeted genetic testing could be useful for patients in whom a cardiologist has established a clinical index of suspicion for BrS based on the patient?s clinical history, family history, and the expressed electrocardiographic (resting 12-lead ECGs and/or provocative drug challenge testing) phenotype. Over the past 20 years, extensive research in this field has allowed better understanding of the pathophysiology, genetic background, and management of BrS even though controversies still exist. In this review article, a background of genetics, the genetic background of BrS, the genotype and phenotype relationship, the role of genetic screening in clinical practice, and the interpretation of the identified genetic variants have been addressed based on this understanding.

SUBMITTER: Juang JJ

PROVIDER: S-EPMC5063259 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Genetics of Brugada syndrome.

Juang Jyh-Ming Jimmy JJ Horie Minoru M

Journal of arrhythmia 20160912 5

In 1992, the Brugada syndrome (BrS) was recognized as a disease responsible for sudden cardiac death, characterized by a right bundle-branch block with ST segment elevation in the leads V1 and V2. This syndrome is highly associated with sudden cardiac death, especially in young males. BrS is currently diagnosed in patients with ST-segment elevation showing type 1 morphology ≥ 2 mm in ≥1 leads among the right precordial leads V1 or V2 positioned in the 2nd, 3rd, or 4th intercostal space, and occu ...[more]

PMID: 27761167

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Project description: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.

Project description:Less than 30% of the cases of Brugada syndrome (BrS) have an identified genetic cause. Of the known BrS-susceptibility genes, loss-of-function mutations in SCN5A or CACNA1C and their auxiliary subunits are most common. On the basis of the recent demonstration that fibroblast growth factor (FGF) homologous factors (FHFs; FGF11-FGF14) regulate cardiac Na(+) and Ca(2+) channel currents, we hypothesized that FHFs are candidate BrS loci.The goal of this study was to test whether FGF12 is a candidate BrS locus.We used quantitative polymerase chain reaction to identify the major FHF expressed in the human ventricle and then queried a phenotype-positive, genotype-negative BrS biorepository for FHF mutations associated with BrS. We queried the effects of an identified mutant with biochemical analyses combined with electrophysiological assessment. We designed a novel rat ventricular cardiomyocyte system in which we swapped the endogenous FHF with the identified mutant and defined its effects on multiple ionic currents in their native milieu and on the cardiac action potential.We identified FGF12 as the major FHF expressed in the human ventricle. In 102 individuals in the biorepository, we identified a single missense mutation in FGF12-B (Q7R-FGF12). The mutant reduced binding to the NaV1.5 C terminus, but not to junctophilin-2. In adult rat cardiac myocytes, Q7R-FGF12, but not wild-type FGF12, reduced Na(+) channel current density and availability without affecting Ca(2+) channel function. Furthermore, the mutant, but not wild-type FGF12, reduced action potential amplitude, which is consistent with a mutant-induced loss of Na(+) channel function.These multilevel investigations strongly suggest that Q7R-FGF12 is a disease-associated BrS mutation. Moreover, these data suggest for the first time that FHF effects on Na(+) and Ca(2+) channels are separable. Most significantly, this study establishes a new method to analyze effects of human arrhythmogenic mutations on cardiac ionic currents.

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Genetics of Brugada syndrome.

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Genetics of Brugada syndrome.

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