Dataset Information

Variants in the SCN5A Promoter Associated With Various Arrhythmia Phenotypes.

ABSTRACT: Mutations in the coding sequence of SCN5A, which encodes the cardiac Na(+) channel ? subunit, have been associated with inherited susceptibility to various arrhythmias. Variable expression of SCN5A is a possible mechanism responsible for this pleiotropic effect; however, it is unknown whether variants in the promoter and regulatory regions of SCN5A also modulate the risk of arrhythmias.We resequenced the core promoter region of SCN5A and the regulatory regions of SCN5A transcription in 1298 patients with arrhythmia phenotypes (atrial fibrillation, n=444; sinus node dysfunction, n=49; conduction disease, n=133; Brugada syndrome, n=583; and idiopathic ventricular fibrillation, n=89). We identified 26 novel rare variants in the SCN5A promoter in 29 patients affected by various arrhythmias (atrial fibrillation, n=6; sinus node dysfunction, n=1; conduction disease, n=3; Brugada syndrome, n=14; idiopathic ventricular fibrillation, n=5). The frequency of rare variants was higher in patients with arrhythmias than in controls. In the alignment with chromatin immunoprecipitation sequencing data, the majority of variants were located at regions bound by transcription factors. Using a luciferase reporter assay, 6 variants (Brugada syndrome, n=3; idiopathic ventricular fibrillation, n=2; conduction disease, n=1) were functionally characterized, and each displayed decreased promoter activity compared with the wild-type sequences. We also identified rare variants in the regulatory region that were associated with atrial fibrillation, and the variant decreased promoter activity.Variants in the core promoter region and the transcription regulatory region of SCN5A were identified in multiple arrhythmia phenotypes, consistent with the idea that altered SCN5A transcription levels modulate susceptibility to arrhythmias.

SUBMITTER: Yagihara N

PROVIDER: S-EPMC5079027 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Variants in the SCN5A Promoter Associated With Various Arrhythmia Phenotypes.

Yagihara Nobue N Watanabe Hiroshi H Barnett Phil P Duboscq-Bidot Laetitia L Thomas Atack C AC Yang Ping P Ohno Seiko S Hasegawa Kanae K Kuwano Ryozo R Chatel Stéphanie S Redon Richard R Schott Jean-Jacques JJ Probst Vincent V Koopmann Tamara T TT Bezzina Connie R CR Wilde Arthur A M AA Nakano Yukiko Y Aiba Takeshi T Miyamoto Yoshihiro Y Kamakura Shiro S Darbar Dawood D Donahue Brian S BS Shigemizu Daichi D Tanaka Toshihiro T Tsunoda Tatsuhiko T Suda Masayoshi M Sato Akinori A Minamino Tohru T Endo Naoto N Shimizu Wataru W Horie Minoru M Roden Dan M DM Makita Naomasa N

Journal of the American Heart Association 20160913 9

<h4>Background</h4>Mutations in the coding sequence of SCN5A, which encodes the cardiac Na(+) channel α subunit, have been associated with inherited susceptibility to various arrhythmias. Variable expression of SCN5A is a possible mechanism responsible for this pleiotropic effect; however, it is unknown whether variants in the promoter and regulatory regions of SCN5A also modulate the risk of arrhythmias.<h4>Methods and results</h4>We resequenced the core promoter region of SCN5A and the regulat ...[more]

PMID: 27625342

Similar Datasets

Project description:ImportanceLarge-scale DNA sequencing identifies incidental rare variants in established Mendelian disease genes, but the frequency of related clinical phenotypes in unselected patient populations is not well established. Phenotype data from electronic medical records (EMRs) may provide a resource to assess the clinical relevance of rare variants.ObjectiveTo determine the clinical phenotypes from EMRs for individuals with variants designated as pathogenic by expert review in arrhythmia susceptibility genes.Design, setting, and participantsThis prospective cohort study included 2022 individuals recruited for nonantiarrhythmic drug exposure phenotypes from October 5, 2012, to September 30, 2013, for the Electronic Medical Records and Genomics Network Pharmacogenomics project from 7 US academic medical centers. Variants in SCN5A and KCNH2, disease genes for long QT and Brugada syndromes, were assessed for potential pathogenicity by 3 laboratories with ion channel expertise and by comparison with the ClinVar database. Relevant phenotypes were determined from EMRs, with data available from 2002 (or earlier for some sites) through September 10, 2014.ExposuresOne or more variants designated as pathogenic in SCN5A or KCNH2.Main outcomes and measuresArrhythmia or electrocardiographic (ECG) phenotypes defined by International Classification of Diseases, Ninth Revision (ICD-9) codes, ECG data, and manual EMR review.ResultsAmong 2022 study participants (median age, 61 years [interquartile range, 56-65 years]; 1118 [55%] female; 1491 [74%] white), a total of 122 rare (minor allele frequency <0.5%) nonsynonymous and splice-site variants in 2 arrhythmia susceptibility genes were identified in 223 individuals (11% of the study cohort). Forty-two variants in 63 participants were designated potentially pathogenic by at least 1 laboratory or ClinVar, with low concordance across laboratories (Cohen κ = 0.26). An ICD-9 code for arrhythmia was found in 11 of 63 (17%) variant carriers vs 264 of 1959 (13%) of those without variants (difference, +4%; 95% CI, -5% to +13%; P = .35). In the 1270 (63%) with ECGs, corrected QT intervals were not different in variant carriers vs those without (median, 429 vs 439 milliseconds; difference, -10 milliseconds; 95% CI, -16 to +3 milliseconds; P = .17). After manual review, 22 of 63 participants (35%) with designated variants had any ECG or arrhythmia phenotype, and only 2 had corrected QT interval longer than 500 milliseconds.Conclusions and relevanceAmong laboratories experienced in genetic testing for cardiac arrhythmia disorders, there was low concordance in designating SCN5A and KCNH2 variants as pathogenic. In an unselected population, the putatively pathogenic genetic variants were not associated with an abnormal phenotype. These findings raise questions about the implications of notifying patients of incidental genetic findings.

Dataset Information

Variants in the SCN5A Promoter Associated With Various Arrhythmia Phenotypes.

Publications

Variants in the SCN5A Promoter Associated With Various Arrhythmia Phenotypes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets