The global distribution of the p.R1193Q polymorphism in the SCN5A gene

Matsusue, Aya; Yuasa, Isao; Umetsu, Kazuo; Nakayashiki, Nori; Dewa, Koji; Nishimukai, Hiroaki; Kashiwagi, Masayuki; Hara, Kenji; Waters, Brian; Takayama, Mio; Ikematsu, Natsuki; Kubo, Shin‐ichi

doi:10.1016/j.legalmed.2015.07.010

Cited by 8 publications

(5 citation statements)

References 26 publications

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“…The frequency of R1193Q in this study is higher than that in the Thai general population (0.075 versus 0.0395), because only symptomatic BrS cases (majority with history of SCA) are included in the present study. 15 Moreover, the R1193Q in the present study is associated with cardiac conduction delay with evidence of a longer PR, a wider QRS duration, and a significantly higher frequency of R1193Q was observed in the BrS patients receiving appropriate ICD shock therapy more than those who did not receive the ICD shock therapy (31.25% versus 4.35%; P=0.029), as shown in Table 1. Ohkubo et al also reported prolonged QRS duration of more than 120 ms, as measured on a standard ECG, that is associated with life-threatening ventricular arrhythmia in BrS.…”

Section: Discussionsupporting

confidence: 53%

SCN5A Genetic 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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Section: Discussionsupporting

confidence: 53%

SCN5A Genetic Polymorphisms Associated With Increased Defibrillator Shocks in Brugada Syndrome

Makarawate

Chaosuwannakit

Vannaprasaht

et al. 2017

JAHA

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“…With the development of next-generation sequencing (NGS), population frequency studies can be conducted faster and on a larger scale, and the pathogenicity of variants can be evaluated on the basis of ancestry-specific references. For example, the SCN5A p.R1193Q substitution, which accelerates the inactivation of sodium channels (Vatta et al, 2002), is now considered to be a disease predisposition allele rather than a causative mutation in Asian populations; its allele frequency in this ancestry is as high as 0.05 (Matsusue et al, 2016), which is much higher than the disease prevalence rate. Another example involves SCN5A c.2893C > T (p.R965C), which exhibits major differences in allele frequency among ancestries (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the allele frequency of a pathogenic variant of BrS is expected to be lower than 0.000075, implying that the pathogenicity of any variants with allele frequencies higher than this value may require careful interpretation. However, in vitro studies have revealed that some variants are associated with functional alterations (Matsusue et al, 2016). Such cases should be treated as disease predisposition alleles rather than totally excluding their pathogenic role.…”

Section: Methodsmentioning

confidence: 99%

Impact of Ancestral Differences and Reassessment of the Classification of Previously Reported Pathogenic Variants in Patients With Brugada Syndrome in the Genomic Era: A SADS-TW BrS Registry

Chen

Lin

et al. 2019

Front. Genet.

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Brugada syndrome (BrS) is a heritable disease that results in sudden cardiac death. In the exome/genomic era, certain reported pathogenic variants in some genetic diseases have been reclassified as benign owing to their high frequency in some ancestries. In the present study, we comprehensively reassessed all previously reported pathogenic variants of BrS. We collected all pathogenic variants of BrS reported in the Human Gene Mutation Database and ClinVar throughout April 2017. We compared the minor allele frequency (MAF) of each variant among different ancestries by searching public whole-genome and exome databases. After considering the maximum credible allele frequency, variants with a MAF ≥ 0.001 were considered to be of questionable pathogenicity. We also investigated the percentage of SCN5A variants with a MAF ≥ 0.001 in 124 BrS patients from the Han Chinese population. We collected a total of 440 BrS variants, of which 18 had a MAF ≥ 0.001. There was a greater percentage of non-SCN5A variants with a MAF ≥ 0.001 than of SCN5A variants (21.8 versus 1.6%, p < 0.0001). There were fewer frameshift and nonsense mutations than missense mutations (0.9 versus 5.6%, p = 0.032). Of the 18 variants, 14 (77.8%) were present only in the reference Asian population. In our cohort, we identified two SCN5A variants (p.A226V and p.V1340I) with MAFs ≥ 0.001 (0.45%). In conclusion, ancestral differences are important when considering the pathogenicity of BrS variants, especially in the case of missense variants and non-SCN5A variants, which may be pathogenic in some ancestries but only disease-predisposing in others.

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“…For example, Ackerman et al (2004) reported that the allele frequency of R1193Q was 8% in Asians, 0.3% in white, and no R1193Q was found in black and Hispanic healthy individuals. More recently, Matsusue et al (2016) investigated more than 4000 DNA samples and found that R1193Q was detected in most Asian populations, but was sporadically observed or absent in European and African populations. In the present study, the allele frequency of R1193Q was 6.7%.…”

Section: Discussionmentioning

confidence: 99%

“Pill-in-the-Pocket” Treatment of Propafenone Unmasks ECG Brugada Pattern in an Atrial Fibrillation Patient With a Common SCN5A R1193Q Polymorphism

Ruan

Liu

et al. 2019

Front. Physiol.

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Background: “Pill-in-the-pocket” (PIP) treatment with type IC drugs for cardioversion of recent-onset atrial fibrillation (AF) has been recommended in guidelines. Major adverse effects have been often reported, and the underlying mechanisms are proposed to be associated with the genetic backgrounds. Methods and Results: A male patient was treated with PIP approach (propafenone 600 mg.po) for the conversion of new onset AF. His symptoms got worse and referred to emergency room; ECG showed a typical Brugada syndrome (BrS) type I ECG pattern with sinus rhythm. Genetic screening identified a common SCN5A polymorphism R1193Q. Propafenone blockade of I Na was studied in HEK293 cells expressed SCN5A R1193Q channel and WT channel using patch clamp techniques. There was no significant difference in peak current and steady-state gating parameters between R1193Q and WT at baseline. At clinically relevant concentration of 2 μmol/L propafenone, use-dependent block (UDB) of I Na was more pronounced in R1193Q versus WT (44.2 ± 7.2 versus 24.8 ± 5.7% at the frequency of 2 Hz, P < 0.05); IC 50 of UDB was 2.9 ± 0.7 μmol/L for R1193Q and 8.1 ± 1.8 μmol/L for WT, respectively. Propafenone produced more left shift of steady-state inactivation and slower recovery from inactivation in R1193Q compared with WT. Conclusion: A common SCN5A polymorphism R1193Q enhances UDB by propafenone and predisposes the patients to drug-induced BrS with PIP treatment. Our data suggest that R1193Q polymorphism is likely to be a genetic marker for the major adverse effects associated with propafenone PIP approach for AF patients’ management. Ajmaline challenge to rule out the presence of BrS should be considered prior to propafenone PIP therapy in AF patients who are identified to have R1193Q polymorphism.

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The global distribution of the p.R1193Q polymorphism in the SCN5A gene

Cited by 8 publications

References 26 publications

SCN5A Genetic Polymorphisms Associated With Increased Defibrillator Shocks in Brugada Syndrome

SCN5A Genetic Polymorphisms Associated With Increased Defibrillator Shocks in Brugada Syndrome

Impact of Ancestral Differences and Reassessment of the Classification of Previously Reported Pathogenic Variants in Patients With Brugada Syndrome in the Genomic Era: A SADS-TW BrS Registry

“Pill-in-the-Pocket” Treatment of Propafenone Unmasks ECG Brugada Pattern in an Atrial Fibrillation Patient With a Common SCN5A R1193Q Polymorphism

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