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Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome.

ABSTRACT: BrS is an inherited sudden cardiac death syndrome. Less than 35% of BrS probands have genetically identified pathogenic variants. Recent evidence has implicated SCN10A, a neuronal sodium channel gene encoding Nav1.8, in the electrical function of the heart.The purpose of this study was to test the hypothesis that SCN10A variants contribute to the development of Brugada syndrome (BrS).Clinical analysis and direct sequencing of BrS susceptibility genes were performed for 150 probands and family members as well as >200 healthy controls. Expression and coimmunoprecipitation studies were performed to functionally characterize the putative pathogenic mutations.We identified 17 SCN10A mutations in 25 probands (20 male and 5 female); 23 of the 25 probands (92.0%) displayed overlapping phenotypes. SCN10A mutations were found in 16.7% of BrS probands, approaching our yield for SCN5A mutations (20.1%). Patients with BrS who had SCN10A mutations were more symptomatic and displayed significantly longer PR and QRS intervals compared with SCN10A-negative BrS probands. The majority of mutations localized to the transmembrane-spanning regions. Heterologous coexpression of wild-type (WT) SCN10A with WT-SCN5A in HEK cells caused a near doubling of sodium channel current compared with WT-SCN5A alone. In contrast, coexpression of SCN10A mutants (R14L and R1268Q) with WT-SCN5A caused a 79.4% and 84.4% reduction in sodium channel current, respectively. The coimmunoprecipitation studies provided evidence for the coassociation of Nav1.8 and Nav1.5 in the plasma membrane.Our study identified SCN10A as a major susceptibility gene for BrS, thus greatly enhancing our ability to genotype and risk stratify probands and family members.

SUBMITTER: Hu D

PROVIDER: S-EPMC4116276 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome.

Hu Dan D Barajas-Martínez Hector H Pfeiffer Ryan R Dezi Fabio F Pfeiffer Jenna J Buch Tapan T Betzenhauser Matthew J MJ Belardinelli Luiz L Kahlig Kristopher M KM Rajamani Sridharan S DeAntonio Harry J HJ Myerburg Robert J RJ Ito Hiroyuki H Deshmukh Pramod P Marieb Mark M Nam Gi-Byoung GB Bhatia Atul A Hasdemir Can C Haïssaguerre Michel M Veltmann Christian C Schimpf Rainer R Borggrefe Martin M Viskin Sami S Antzelevitch Charles C

Journal of the American College of Cardiology 20140701 1

<h4>Background</h4>BrS is an inherited sudden cardiac death syndrome. Less than 35% of BrS probands have genetically identified pathogenic variants. Recent evidence has implicated SCN10A, a neuronal sodium channel gene encoding Nav1.8, in the electrical function of the heart.<h4>Objectives</h4>The purpose of this study was to test the hypothesis that SCN10A variants contribute to the development of Brugada syndrome (BrS).<h4>Methods</h4>Clinical analysis and direct sequencing of BrS susceptibili ...[more]

PMID: 24998131

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Project description:In 1992, the Brugada syndrome (BrS) was recognized as a disease responsible for sudden cardiac death, characterized by a right bundle-branch block with ST segment elevation in the leads V1 and V2. This syndrome is highly associated with sudden cardiac death, especially in young males. BrS is currently diagnosed in patients with ST-segment elevation showing type 1 morphology ≥ 2 mm in ≥1 leads among the right precordial leads V1 or V2 positioned in the 2nd, 3rd, or 4th intercostal space, and occurring either spontaneously or after a provocative drug test by the intravenous administration of Class I antiarrhythmic drugs. With accumulated findings, the BrS inheritance model is believed to be an autosomal dominant inheritable model with incomplete penetrance, although most patients with BrS were sporadic cases. SCN5A, which was identified as the first BrS-associated gene in 1998, has emerged as the most common gene associated with BrS, and more than 10 BrS-associated genes have been identified thereafter. Mutation-specific genetic testing is recommended for the family members and appropriate relatives following the identification of BrS-causative mutations in an index patient. In addition, comprehensive or BrS1 (SCN5A) targeted genetic testing could be useful for patients in whom a cardiologist has established a clinical index of suspicion for BrS based on the patient׳s clinical history, family history, and the expressed electrocardiographic (resting 12-lead ECGs and/or provocative drug challenge testing) phenotype. Over the past 20 years, extensive research in this field has allowed better understanding of the pathophysiology, genetic background, and management of BrS even though controversies still exist. In this review article, a background of genetics, the genetic background of BrS, the genotype and phenotype relationship, the role of genetic screening in clinical practice, and the interpretation of the identified genetic variants have been addressed based on this understanding.

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Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome.

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Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome.

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