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Genetic diversity of SCN5A gene and its possible association with the concealed form of Brugada syndrome development in Polish group of patients.

ABSTRACT: Brugada Syndrome (BS) is an inherited channelopathy associated with a high incidence of sudden cardiac death. The paper presents the discovery of new genetic variants of SCN5A gene which might be associated with the development of a concealed form of Brugada Syndrome. The study involved a group of 59 patients (37 men) with suspected concealed form of Brugada Syndrome. Pharmacological provocation with intravenous ajmaline administration was performed. Six patients with positive test results were subjected to molecular analysis of SCN5A gene with MSSCP method. Additionally, MSSCP genotyping was performed for samples obtained from the family members with Brugada Syndrome, despite the fact that they had negative ajmaline challenge test results. Genetic examinations of the SCN5A gene at 6 positive patients showed 6 known polymorphisms, 8 new single nucleotide point (SNP) variants located at exons, and 12 new single nucleotide point variants located at introns. Among new SNPs localized in SCN5A gene exons three SNPs affected the protein sequence.

SUBMITTER: Uzieblo-Zyczkowska B

PROVIDER: S-EPMC4220633 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Genetic diversity of SCN5A gene and its possible association with the concealed form of Brugada syndrome development in Polish group of patients.

Uziębło-Życzkowska Beata B Gielerak Grzegorz G Siedlecki Paweł P Pająk Beata B

BioMed research international 20141020

Brugada Syndrome (BS) is an inherited channelopathy associated with a high incidence of sudden cardiac death. The paper presents the discovery of new genetic variants of SCN5A gene which might be associated with the development of a concealed form of Brugada Syndrome. The study involved a group of 59 patients (37 men) with suspected concealed form of Brugada Syndrome. Pharmacological provocation with intravenous ajmaline administration was performed. Six patients with positive test results were ...[more]

PMID: 25401102

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Project description:BackgroundBrugada syndrome (BrS) is a severe inherited arrhythmia syndrome that can be unmasked by fever.MethodsA multicentre clinical analysis was performed in 261 patients diagnosed with fever-induced BrS, including 198 (75.9%) and 27 (10.3%) patients who received next-generation genetic sequencing and epicardial arrhythmogenic substrate (AS) mapping, respectively.FindingsIn fever-induced BrS patients, pathogenic or likely pathogenic (P/LP) SCN5A variant carriers developed fever-induced BrS at a younger age, and more often in females and those of Caucasian descent. They exhibited significant electrophysical abnormalities, including a larger epicardial AS area, and more prolonged abnormal epicardial electrograms. During a median follow-up of 50.5 months (quartiles 32.5-81.5 months) after the diagnosis, major cardiac events (MCE) occurred in 27 (14.4%) patients. Patients with P/LP SCN5A variants had a higher ratio of MCE compared with the rest. Additionally, history of syncope, QRS duration, and Tpe interval could also predict an increased risk for future MCE according to univariate analysis. Multivariate analysis indicated that only P/LP SCN5A variants were independent significant predictors of MCE. Computational structural modelling showed that most variants are destabilizing, suggesting that Nav1.5 structure destabilization caused by SCN5A missense variants may contribute to fever-induced BrS.InterpretationIn our cohort, P/LP SCN5A variant carriers with fever-induced BrS are more prevalent among patients of Caucasian descent, females, and younger patients. These patients exhibit aggressive electrophysiological abnormalities and worse outcome, which warrants closer monitoring and more urgent management of fever.FundingThe current work was supported by the National Natural Science Foundation Project of China (Nos. 82270332 & 81670304), The Fundamental Research Funds for the Central Universities of China - Independent Research Project of Wuhan University (No. 2042022kf1217) from China; the National Institutes of Health of USA [NIH R56 (HL47678), NIH R01 (HL138103), and NIH R01 (HL152201)], the W. W. Smith Charitable Trust and the Wistar and Martha Morris Fund, Sharpe-Strumia Research Foundation, the American Heart Association Postdoctoral Fellowship (20POST35220002) from United States; the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences (PREDICT2) from the Netherlands.

Dataset Information

Genetic diversity of SCN5A gene and its possible association with the concealed form of Brugada syndrome development in Polish group of patients.

Publications

Genetic diversity of SCN5A gene and its possible association with the concealed form of Brugada syndrome development in Polish group of patients.

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