Comparable clinical characteristics in Brugada syndrome patients harboring SCN5A or novel SCN10A variants

Monasky, Michelle M.; Micaglio, Emanuele; Vicedomini, Gabriele; Locati, Emanuela H.; Ciconte, Giuseppe; Giannelli, Luigi; Giordano, Federica; Crisà, Simonetta; Vecchi, Mattia; Borrelli, Valeria; Ghiroldi, Andrea; D'Imperio, Sara; Resta, Chiara Di; Benedetti, Sara; Ferrari, Maurizio; Santinelli, Vincenzo; Anastasia, Luigi; Pappone, Carlo

doi:10.1093/europace/euz186

Cited by 18 publications

(18 citation statements)

References 18 publications

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“…In fact, the normal QRS complex in a human ECG is regulated by several genes, some of them already studied as possible candidates for BrS and, more generally, for familial arrhythmic disorders [76]. Interestingly, this article [76] proposed SCN10A as the major QRS regulatory gene and, about eight years later, our research group demonstrated that a comparison between SCN5A and SCN10A Brugada patients is possible [77].…”

Section: Sodium Channel Mutationsmentioning

confidence: 87%

“…Routinely, in silico predictions are used to ascertain the likelihood of the pathogenicity of a particular variant. However, these analyses tools are often unreliable or result in an uncertain significance of a particular variant [77]. Thus, family segregation analysis and functional studies are still necessary to understand the likelihood of pathogenicity of a particular variant, even after the performance of in silico studies.…”

Section: Sodium Channel Mutationsmentioning

confidence: 99%

“…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]. This is consistent with functional studies performed in human-induced pluripotent stem cell-derived cardiomyocytes, in which single-cell phenotype features of BrS were seen in cells from a patient harboring the variants NM_006514.3:c.3803G>A and NM_006514.3:c.3749G>A in the SCN10A gene [47].…”

Section: Sodium Channel Mutationsmentioning

confidence: 99%

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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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Section: Sodium Channel Mutationsmentioning

confidence: 87%

Section: Sodium Channel Mutationsmentioning

confidence: 99%

Section: Sodium Channel Mutationsmentioning

confidence: 99%

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Brugada Syndrome: Oligogenic or Mendelian Disease?

Monasky

Micaglio

Ciconte

et al. 2020

IJMS

Self Cite

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“…Single nucleotide polymorphisms (SNPs) that may play a role in high risk of VA and SCD diseases like atrial fibrillation (AF) 11 and BrS have been identified by genomewide association studies (GWAS) on the PITX2, 12 SCN5A, SCN10A, and HEY2 genes. 13 More recently, some of them have been involved in Brs, 14 long QT syndrome and SCD. 15 In this in mind, we designed a case-control study using 4 SNPs previously associated with BrS (rs11708996, rs10428132 and rs9388451) and AF (rs2200733) to test their influence on the physiopathology of cardiac arrhythmias in patients with structural heart disease, aiming at finding a genetic marker that could be used as a general predictor of SCD.…”

Section: Introductionmentioning

confidence: 99%

Single nucleotide polymorphisms of SCN5A and SCN10A genes increase the risk of ventricular arrhythmias during myocardial infarction

Foddha¹,

Bouzidi²,

Foddha³

et al. 2020

Adv Clin Exp Med

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Background. Coronary artery disease (CAD) and its ultimate consequence − myocardial infarction (MI) − are major causes of sudden cardiac death (SCD). Previous studies have demonstrated the role of genetic polymorphisms in the risk of SCD and ventricular arrhythmia (VA) during MI. Objectives. To investigate the association between single nucleotide polymorphisms (SNPs) of genes implicated in congenital cardiac arrhythmias and the risk of developing VA in the context of MI. Material and methods. We performed a case-control study in which we genotyped 4 SNPs (rs11708996, rs10428132, rs9388451, and rs2200733) in 469 subjects using amplification refractory mutation system (ARMS) and a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). These SNPs are located in the SCN5A, SCN10A, HEY2, and PITX2 genes, respectively. We first compared 70 patients who had developed VA in the context of MI with 141 healthy controls; next, we compared VA patients with 258 MI patients who did not develop VA during a 1-year follow up. The statistical analyses were adjusted for sex and age. Results. Compared to the controls, 2 polymorphisms were significantly associated with the development of VA during MI, located in SCN5A rs11708996 (p = 0.001) and SCN10A rs10428132 (p = 0.001). Similar results were found when comparing VA cases with patients without VA. No associations of HEY2 and PITX2 polymorphisms were observed. Conclusions. Our results suggest that the rs11708996 and rs10428132 polymorphisms of the SCN5A and SCN10A genes may contribute to an elevated risk of developing VA in the context of MI. The associated alleles or genotypes may be used to predict the risk, and thus prevent eventual SCD.

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“…Novel mutations in the SCN5A gene and their likely causative role in BrS have been of recent interest [9][10][11][12][13][14][15], as well as new candidate genes [13,16,17]. Most studies have reported autosomal dominant inheritance with incomplete penetrance [18][19][20], with a few suggesting a recessive or X linked inheritance [21,22] and a possible involvement of mitochondrial mutations [23].…”

Section: Introductionmentioning

confidence: 99%

Novel SCN5A p.V1429M Variant Segregation in a Family with Brugada Syndrome

Monasky

Micaglio

Ciconte

et al. 2020

IJMS

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Brugada syndrome (BrS) is diagnosed by the presence of an elevated ST-segment and can result in sudden cardiac death. The most commonly found mutated gene is SCN5A, which some argue is the only gene that has been definitively confirmed to cause BrS, while the potential causative effect of other genes is still under debate. While the issue of BrS genetics is currently a hot topic, current knowledge is not able to result in molecular confirmation of over half of BrS cases. Therefore, it is difficult to develop research models with wide potential. Instead, the clinical genetics first need to be better understood. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.4285G>A (p.Val1429Met) in the SCN5A gene, and demonstrate its segregation with BrS, suggesting a pathogenic effect. These results provide the first disease association with this variant and are crucial clinical data to communicate to basic scientists, who could perform functional studies to better understand the molecular effects of this clinically-relevant variant in BrS.

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Comparable clinical characteristics in Brugada syndrome patients harboring SCN5A or novel SCN10A variants

Cited by 18 publications

References 18 publications

Brugada Syndrome: Oligogenic or Mendelian Disease?

Brugada Syndrome: Oligogenic or Mendelian Disease?

Single nucleotide polymorphisms of SCN5A and SCN10A genes increase the risk of ventricular arrhythmias during myocardial infarction

Novel SCN5A p.V1429M Variant Segregation in a Family with Brugada Syndrome

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