Clinical Characteristics of
            <i>SCN5A</i>
            p.R965C Carriers: A Common Founder Variant Predisposing to Brugada Syndrome in Thailand

Chimparlee, Nitinan; Prechawat, Somchai; Khongphatthanayothin, Apichai; Mauleekoonphairoj, John; Lekchuensakul, Sarin; Wongcharoen, Wanwarang; Makarawate, Pattarapong; Sahasatas, Dujdao; Krittayaphong, Rungroj; Amnueypol, Montawatt; Anannab, Alisara; Ngarmukos, Tachapong; Vardhanabhuti, Saran; Sutjaporn, Boosamas; Wandee, Pharawee; Veerakul, Gumpanart; Bezzina, Connie R.; Poovorawan, Yong; Nademanee, Koonlawee

doi:10.1161/circgen.120.003229

Cited by 4 publications

(7 citation statements)

References 5 publications

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“…The c.1890+14G>A variant was found in the intronic region and was predicted benign on the ClinVar database (rs145427253) (Duzkale et al, 2013 ). Other variants were determined to occur at 28.57% (6/21) on the internal domain linker, such as DI‐II (c.1712G>C (S571T), c.1975C>T (R659W)), DII‐III (c.2893C>T (R965C), c.3338C>T (A1113V), c.3578G>A (R1193Q)), and DIII‐IV (c.4534C>T (R1511W)) (Abe et al, 2018 ; Chimparlee et al, 2021 ; Kapplinger et al, 2009 , 2010 ; Meregalli et al, 2009 ; Shen et al, 2022 ). Of these variants, c.3338C>T (A1113V) and c.3578G>A (R1193Q) were predicted as benign, and damage was evaluated in the other.…”

Section: Discussionmentioning

confidence: 99%

In silico validation revealed the role of SCN5A mutations and their genotype–phenotype correlations in Brugada syndrome

Pham,

Dang,

et al. 2023

Molec Gen & Gen Med

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BackgroundBrugada syndrome (BrS) is a rare genetic disease that causes sudden cardiac death (SCD) and arrhythmia. SCN5A pathogenic variants (about 30% of diagnosed patients) are responsible for BrS.AimsLack of knowledge regarding molecular characteristics and the correlation between genotype and phenotype interfere with the risk stratification and finding the optimal treatment in Vietnam. Therefore, we identified SCN5A variants and evaluated the genotype–phenotype correlation of BrS on 117 Vietnamese probands.Materials and MethodsThe clinical characteristics and blood samples of BrS patients were collected. To determine SCN5A variants, Sanger sequencing was conducted, and subsequently, these variants were analyzed by bioinformatic tools.ResultsIn this cohort, the overall rate of detected variants in SCN5A was 25.6%, which could include both pathogenic and benign variants. In genetic testing, 21 SCN5A variants were identified, including eight novels and 15 published variants. Multiple bioinformatic tools were used to predict variant effect with c.551A>G, c.1890+14G>A, c.3338C>T, c.3578G>A, and c.5484C>T as benign, while other variants were predicted as disease‐causing. The family history of SCD (risk ratio [RR] = 4.324, 95% CI: 2.290–8.269, p < 0.001), syncope (RR = 3.147, 95% CI: 1.668–5.982, p = 0.0004), and ventricular tachycardia/ventricular fibrillation (RR = 3.406, 95% CI: 1.722–5.400, p = 0.0035) presented a significantly higher risk in the SCN5A (+) group, consisting of individuals carrying any variant in the SCN5A gene, compared to SCN5A (−) individuals.ConclusionThe results contribute to clarifying the impact of SCN5A variants on these phenotypes. Further follow‐up studies need to be carried out to understand the functional effects of these SCN5A variants on the severity of BrS.

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Section: Discussionmentioning

confidence: 99%

In silico validation revealed the role of SCN5A mutations and their genotype–phenotype correlations in Brugada syndrome

Pham,

Dang,

et al. 2023

Molec Gen & Gen Med

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“…Haplotype reconstruction was carried out in SCN5A p.R965C carriers and 574 Thais without this variant. 24 All SCN5A p.R965C carriers had the 70-kb haplotype at the genomic region up- and downstream to the location of this variant, while it was found in only 16 of 574 in the control group, suggesting that all 23 SCN5A p.R965C carriers have the same ancestor. Thus, we concluded that this variant is likely a result of founder mutation and may be one reason for high prevalence of BrS in Thailand.…”

Section: Suds/brs Genetic Studies In Thailandmentioning

confidence: 95%

“…Our study group comprised 7 hospitals in Thailand (NCT04232787), and we found that out of the 151 BrS cases and 358 controls, 12 (10 cases and 2 controls) carried the SCN5A p.R965C variant. 24 Of these 12 probands, we were able to contact 6 families, screening 63 family members including first-, second-, and third-degree relatives (42.9% male, 47 ± 19 years of age) and found an additional 11 SCN5A p.R965C carriers, 1 of whom had BrS. Thus, of 23 carriers of SCN5A R965C, 11 had BrS; 7 (64%) of the 11 BrS patients were symptomatic, including 5 VF and 2 unexplained syncope (n = 2), whereas all variant carriers without BrS were asymptomatic.…”

Section: Suds/brs Genetic Studies In Thailandmentioning

confidence: 99%

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Brugada syndrome in Thailand: Three decades of progress

Veerakul¹,

Khongphatthanayothin²,

Nademanee³

2022

Heart Rhythm O2

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“…The detected variant was previously described in ClinVar (variation ID: 67763). While SCN5A p.R965C variant is rare (minor allele frequency = 0.00001) in the general population database (gnomAD-ALL), its frequency is relatively higher in Asian populations, particularly enriched in the Thai population (0.00188), possibly as a result of the funder effect (11,12). Its deleterious effect as predicted by silico predictions, conservation analysis and published functional studies (13).…”

Section: Analysis Of Genetic Variantsmentioning

confidence: 99%

Case Report: Lacosamide unmasking SCN5A-associated Brugada syndrome in a young female with epilepsy

Shen,

Wu,

Lin

et al. 2024

Front. Cardiovasc. Med.

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BackgroundLacosamide is frequently used as a mono- or adjunctive therapy for the treatment of adults with epilepsy. Although lacosamide is known to act on both neuronal and cardiac sodium channels, potentially leading to cardiac arrhythmias, including Brugada syndrome (BrS), its adverse effects in individuals with genetic susceptibility are less understood.CaseWe report a 33-year-old female with underlying epilepsy who presented to the emergency department with a four-day history of seizure clusters, and was initially treated with lacosamide therapy. During the intravenous lacosamide infusion, the patient developed sudden cardiac arrest caused by ventricular arrhythmias necessitating resuscitation. Of note, the patient had a family history of sudden cardiac death. Workup including routine laboratory results, 12-lead electrocardiogram (ECG), echocardiogram, and coronary angiogram was non-specific. However, a characteristic type 1 Brugada ECG pattern was identified by ajmaline provocation testing; thus, confirming the diagnosis of BrS. Subsequently, the genotypic diagnosis was confirmed by Sanger sequencing, which revealed a heterozygous mutation (c.2893C>T, p.Arg965Cys) in the SCN5A gene. Eventually, the patient underwent implantable cardioverter-defibrillator implantation and was discharged with full neurological recovery.ConclusionThis case highlights a rare but lethal adverse event associated with lacosamide treatment in patients with genetic susceptibility. Further research is warranted to investigate the interactions between lacosamide and SCN5A variants.

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Clinical Characteristics of SCN5A p.R965C Carriers: A Common Founder Variant Predisposing to Brugada Syndrome in Thailand

Cited by 4 publications

References 5 publications

In silico validation revealed the role of SCN5A mutations and their genotype–phenotype correlations in Brugada syndrome

In silico validation revealed the role of SCN5A mutations and their genotype–phenotype correlations in Brugada syndrome

Brugada syndrome in Thailand: Three decades of progress

Case Report: Lacosamide unmasking SCN5A-associated Brugada syndrome in a young female with epilepsy

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