Ethnic differences in patients with Brugada syndrome and arrhythmic events: New insights from Survey on Arrhythmic Events in Brugada Syndrome

Milman, Anat; Andorin, Antoine; Postema, Pieter G.; Gourraud, Jean‐Baptiste; Sacher, Frédéric; Mabo, Philippe; Kim, Sung‐Hwan; Maeda, Shingo; Takahashi, Yoshihide; Kamakura, Tsukasa; Aiba, Takeshi; Conte, Giulio; Juang, Jimmy J.M.; Leshem, Eran; Michowitz, Yoav; Fogelman, Rami; Hochstadt, Aviram; Mizusawa, Yuka; Giustetto, Carla; Arbelo, Elena; Huang, Zhengrong; Corrado, Domenico; Delise, Pietro; Allocca, Giuseppe; Takagi, Masahiko; Wijeyeratne, Yanushi D.; Mazzanti, Andrea; Brugada, Ramón; Casado-Arroyo, Rubén; Champagne, Jean; Calò, Leonardo; Sarquella‐Brugada, Georgia; Jespersen, Camilla H B; Tfelt-Hansen, Jacob; Veltmann, Christian; Priori, Silvia G.; Behr, Elijah R.; Yan, Gan‐Xin; Brugada, Josép; Gaïta, Fiorenzo; Wilde, Arthur A.M.; Brugada, Pedro; Kusano, Kengo; Hirao, Kazuyuki; Nam, Gi‐Byoung; Probst, Vincent; Belhassen, Bernard

doi:10.1016/j.hrthm.2019.07.003

Cited by 23 publications

(19 citation statements)

References 30 publications

(38 reference statements)

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“…Hap 1/1 and Hap 2/3 are common in some but not all human super-populations Epidemiologic studies have shown differences in the prevalence of Brugada syndrome worldwide. 68 We wondered, therefore, whether the distribution of the risk and protective genotypes varies across human super-populations. For simplification, we focused on Hap 1/1 , Hap 2/3 , and the homozygote genotypes inferred in at least 1 super-population (i.e., Hap 2/2 , Hap 3/3 , Hap 4/4 , Hap 5/5 , and Hap 21/21 [the latter is common in the AFR super-population]; Figures 5A and S3A).…”

Section: Recessive Hap1 Inheritance Associated With An Increased Risk For Brugada Syndromementioning

confidence: 99%

“…74 Notably, the Hap 1/1 genotype is uncommon in the EAS super-population, which is consistent with epidemiologic studies showing that Brugada syndrome cases across the Chinese, Japanese, Taiwanese, and South Korean populations carry fewer deleterious variants than Caucasians in the SCN5A locus. 68 A second relevant observation is the identification of a Brugada-protective noncoding genotype based on haplotypes, Hap 2/3 . Prior studies report protective variants against arrhythmia in the coding regions of the KCNQ1 and SCN5A genes 26,75 and protective variants against Brugada syndrome in a coding region of the SCN10A gene and in a non-coding site downstream the HEY2 gene in the Japanese population.…”

Section: Accessmentioning

confidence: 99%

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Analysis of Brugada syndrome loci reveals that fine-mapping clustered GWAS hits enhances the annotation of disease-relevant variants

Pinsach-Abuin

Olmo²,

Pérez-Agustin³

et al. 2021

Cell Reports Medicine

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Summary Genome-wide association studies (GWASs) are instrumental in identifying loci harboring common single-nucleotide variants (SNVs) that affect human traits and diseases. GWAS hits emerge in clusters, but the focus is often on the most significant hit in each trait- or disease-associated locus. The remaining hits represent SNVs in linkage disequilibrium (LD) and are considered redundant and thus frequently marginally reported or exploited. Here, we interrogate the value of integrating the full set of GWAS hits in a locus repeatedly associated with cardiac conduction traits and arrhythmia, SCN5A - SCN10A . Our analysis reveals 5 common 7-SNV haplotypes (Hap1–5) with 2 combinations associated with life-threatening arrhythmia—Brugada syndrome (the risk Hap 1/1 and protective Hap 2/3 genotypes). Hap1 and Hap2 share 3 SNVs; thus, this analysis suggests that assuming redundancy among clustered GWAS hits can lead to confounding disease-risk associations and supports the need to deconstruct GWAS data in the context of haplotype composition.

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Section: Recessive Hap1 Inheritance Associated With An Increased Risk For Brugada Syndromementioning

confidence: 99%

Section: Accessmentioning

confidence: 99%

Analysis of Brugada syndrome loci reveals that fine-mapping clustered GWAS hits enhances the annotation of disease-relevant variants

Pinsach-Abuin

Olmo²,

Pérez-Agustin³

et al. 2021

Cell Reports Medicine

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“…Although the prevalence has been described as 1:2000 in Western Europe and the USA and 1:500 in Southeast Asia [6], the true prevalence of BrS is unknown, due to the lack of symptoms for even decades in many people and the challenges involved in diagnosis. In Southeast Asia, BrS seems to affect almost exclusively male adults [7]. Pooled analyses indicated that a spontaneous type 1 ECG is an independent risk factor for SCD in males, but not in females, and that male patients are at higher risk of arrhythmic events [8,9].…”

Section: Introductionmentioning

confidence: 99%

Brugada Syndrome: Oligogenic or Mendelian Disease?

Monasky

Micaglio

Ciconte

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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“…Variants in SCN5A account for approximately 30% of cases of Brugada Syndrome. 8 The ClinGen consortium recently affirmed SCN5A as the only gene associated with Brugada Syndrome that meets preset criteria for disease association. 7 A major challenge for the field is to identify which SCN5A variants are disease-associated.…”

Section: High-throughput Approaches To Variant Classificationmentioning

confidence: 99%

“…6 SCN5A loss of function variants are the most common (and in fact, the only ClinGen-validated) genetic cause of BrS, and are present in approximately 30% of cases (BrS1). 7,8 Variants that destabilize fast inactivation of the channel and generate a persistent ("late") current are associated with LQT. 9,10 The risk of sudden cardiac death in BrS patients can be partially prevented, for example with implantable defibrillators.…”

Section: Introductionmentioning

confidence: 99%

High-throughput reclassification ofSCN5Avariants

Glazer

Wada

Bian

et al. 2019

Preprint

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Rationale: Partial or complete loss of function variants in SCN5A are the most common genetic cause of the arrhythmia disorder Brugada Syndrome (BrS1). However, the pathogenicity of SCN5A variants is often unknown or disputed; 80% of the 1,390 SCN5A missense variants observed in at least one individual to date are variants of uncertain significance (VUS). The designation of VUS is a barrier to the use of sequence data in clinical care. Objective:We selected 83 variants for study: 10 previously studied control variants, 10 suspected benign variants, and 63 suspected Brugada Syndrome-associated variants, selected on the basis of their frequency in the general population and in patients with Brugada Syndrome. We used high-throughput automated patch clamping to study the function of the 83 variants, with the goal of reclassifying variants with functional data.Methods and Results: Ten previously studied variants had functional properties concordant with published manual patch clamp data. All 10 suspected benign variants had wildtype-like function. 22 suspected BrS variants had loss of channel function (<10% normalized peak current) and 23 variants had partial loss of function (10-50% normalized peak current). The 73 previously unstudied variants were initially classified as likely benign (n=2), likely pathogenic (n=11), or VUS (n=60). After the patch clamp studies, 16 variants were benign/likely benign, 47 were pathogenic/likely pathogenic, and only 10 were still VUS. 8/22 loss of function variants were partially rescuable by incubation at lower temperature or pretreatment with a sodium channel blocker. Structural modeling identified likely mechanisms for loss of function including altered thermostability, and disruptions to alpha helices, disulfide bonds, or the permeation pore. Conclusions:High-throughput automated patch clamping enabled the reclassification of the majority of tested VUS's in SCN5A.

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Ethnic differences in patients with Brugada syndrome and arrhythmic events: New insights from Survey on Arrhythmic Events in Brugada Syndrome

Cited by 23 publications

References 30 publications

Analysis of Brugada syndrome loci reveals that fine-mapping clustered GWAS hits enhances the annotation of disease-relevant variants

Analysis of Brugada syndrome loci reveals that fine-mapping clustered GWAS hits enhances the annotation of disease-relevant variants

Brugada Syndrome: Oligogenic or Mendelian Disease?

High-throughput reclassification ofSCN5Avariants

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