Flecainide Provocation Reveals Concealed Brugada Syndrome in a Long QT Syndrome Family With a Novel L1786Q Mutation in SCN5A

Kanters, Jørgen K.; Yuan, Lijun; Hedley, Paula L.; Stoevring, Birgitte; Jøns, Christian; Thomsen, Poul Erik Bloch; Grunnet, Morten; Christiansen, Michael; Jespersen, Thomas

doi:10.1253/circj.cj-13-1167

Cited by 23 publications

(16 citation statements)

References 34 publications

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“…In this scenario, the flecainide/ajmaline-induced Brugada phenomenon might represent a marker of electrical instability that might be useful to unmask and stratify subjects carrying mutations at high risk to develop arrhythmia and SD. 30 Moreover, our study confirms the previous evidence that sodium channel blocker drug-induced ST-segment elevation in peripheral leads is an independent predictor for a malignant arrhythmic events.…”

Section: Discussionsupporting

confidence: 90%

“…27, 28 Pathogenic mutations in the SCN5A gene have been associated with several diseases, such as Long QT Syndrome (LQTS), Atrial Fibrillation (AF), Sick Sinus Syndrome (SSS), Progressive Conduction Cardiac Disease (PCCD) and Sudden Infant Death Syndrome (SIDS). 29, 30 Despite most of these diseases belonging to the group of channelopathies without structural heart alterations, SCN5A mutations have also been reported in association with DCM. 31 In this scenario, novel technical approaches, such as NGS, promise to transform clinical practice.…”

Section: Crime Weapon: Molecular Docking Showed That E192k In Tpm1 Comentioning

confidence: 99%

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Next Generation Sequencing and Linkage Analysis for the Molecular Diagnosis of a Novel Overlapping Syndrome Characterized by Hypertrophic Cardiomyopathy and Typical Electrical Instability of Brugada Syndrome

Mango

Luchetti

Sangiuolo

et al. 2016

Circ J

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Section: Discussionsupporting

confidence: 90%

Section: Crime Weapon: Molecular Docking Showed That E192k In Tpm1 Comentioning

confidence: 99%

Next Generation Sequencing and Linkage Analysis for the Molecular Diagnosis of a Novel Overlapping Syndrome Characterized by Hypertrophic Cardiomyopathy and Typical Electrical Instability of Brugada Syndrome

Mango

Luchetti

Sangiuolo

et al. 2016

Circ J

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“…SUNDS, a clinical conundrum in both forensic and clinical medicine, has a strong genetic underpinning based on reported molecular pathological studies . Accumulated evidence suggests that SUNDS is related primarily to cardiac arrhythmia diseases, such as BrS, long QT syndrome, sick sinus syndrome, and cardiac conduction disease . However, we have previously shown that in a Chinese Han population, genetic variants in 39 arrhythmia‐associated genes could only possibly account for a small part of sporadic SUNDS cases, suggesting the existence of unknown susceptible genes.…”

Section: Discussionmentioning

confidence: 94%

Critical Roles of Xirp Proteins in Cardiac Conduction and Their Rare Variants Identified in Sudden Unexplained Nocturnal Death Syndrome and Brugada Syndrome in Chinese Han Population

Huang

Zhang

et al. 2018

JAHA

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BackgroundSudden unexplained nocturnal death syndrome (SUNDS) remains an autopsy negative entity with unclear etiology. Arrhythmia has been implicated in SUNDS. Mutations/deficiencies in intercalated disc components have been shown to cause arrhythmias. Human cardiomyopathy‐associated 1 (XIRP1) and 3 (XIRP2) are intercalated disc–associated, Xin repeats‐containing proteins. Mouse Xirp1 is necessary for the integrity of intercalated disc and for the surface expression of transient outward and delayed rectifier K+ channels, whereas mouse Xirp2 is required for Xirp1 intercalated disc localization. Thus, XIRP1 and XIRP2 may be potentially causal genes for SUNDS.Methods and ResultsWe genetically screened XIRP genes in 134 sporadic SUNDS victims and 22 Brugada syndrome (BrS) cases in a Chinese Han population. We identified 16 rare variants (6 were in silico predicted as deleterious) in SUNDS victims, including a novel variant, XIRP2‐E215K. There were also four rare variants (2 were in silico predicted as deleterious) detected in BrS cases, including a novel variant, XIRP2‐L2718P. Interestingly, among these 20 variants, we detected 2 likely pathogenic variants: a nonsense variant (XIRP2‐Q2875*) and a frameshift variant (XIRP2‐T2238QfsX7). Analyzing available Xirp2 knockout mice, we further found that mouse hearts without Xirp2 exhibited prolonged PR and QT intervals, slow conduction velocity, atrioventricular conduction block, and an abnormal infranodal ventricular conduction system. Whole‐cell patch‐clamp detected altered ionic currents in Xirp2 −/− cardiomyocytes, consistent with the observed association between Xirp2 and Nav1.5/Kv1.5 in co‐immunoprecipitation.ConclusionsThis is the first report identifying likely pathogenic XIRP rare variants in arrhythmogenic disorders such as SUNDS and Brugada syndrome, and showing critical roles of Xirp2 in cardiac conduction.

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“…As a clinical conundrum, SUNDS was thought to be associated mainly with cardiac sodium channel diseases that involve SCN5A mutations, such as BrS [27], Long QT syndrome (LQTS) type 3 [28], sick sinus syndrome (SSS) [29], and cardiac conduction disease (CCD) [30]. SCN10A and SCN5A are located in close proximity to each other in chromosome 3p22 [19], and it was confirmed that SCN10A displayed a similar distribution pattern as SNC5A in mouse hearts [31].…”

Section: Discussionmentioning

confidence: 99%

Association of common and rare variants of SCN10A gene with sudden unexplained nocturnal death syndrome in Chinese Han population

et al. 2016

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Sudden unexplained nocturnal death syndrome (SUNDS) remains an autopsy negative entity with unknown etiology to both forensic pathologists and physicians. The electrocardiogram (ECG) characteristics and clinical phenotype of SUNDS survivors strongly suggest that SUNDS shares some similarities with Brugada syndrome (BrS). Recently, the variants of sodium channel Na 1.8 coding gene SCN10A were identified to be associated with BrS. Here, we investigated the association of SCN10A gene variants with 105 sporadic SUNDS victims and 22 BrS cases in the Chinese Han population. A total of 6 rare mutations and 16 polymorphisms were detected in SUNDS victims. Of the six rare mutations, two were putative pathogenic mutations (F386C and R1263*), one was a likely pathogenic mutation (R14H), and the other three were predicted as benign (R817Q, T1181M, and P1683S). As for the 16 polymorphisms, 1 was a novel polymorphism (c.4144-84G>A) located in intron 24, and the rest were reported previously including one polymorphism (c.2884A>G [I962V]) which showed a statistically significant difference in allele frequency (p = 0.044) between SUNDS and the control group. There were also 5 rare mutations and 15 polymorphisms detected in BrS cases. This is the first report of common and rare variants of SCN10A gene in SUNDS and BrS in the Chinese Han population, which provides the genetic epidemiological evidence that SCN10A may be a novel susceptibility gene for SUNDS and account for approximately 3 % of SUNDS in China.

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Flecainide Provocation Reveals Concealed Brugada Syndrome in a Long QT Syndrome Family With a Novel L1786Q Mutation in SCN5A

Cited by 23 publications

References 34 publications

Next Generation Sequencing and Linkage Analysis for the Molecular Diagnosis of a Novel Overlapping Syndrome Characterized by Hypertrophic Cardiomyopathy and Typical Electrical Instability of Brugada Syndrome

Next Generation Sequencing and Linkage Analysis for the Molecular Diagnosis of a Novel Overlapping Syndrome Characterized by Hypertrophic Cardiomyopathy and Typical Electrical Instability of Brugada Syndrome

Critical Roles of Xirp Proteins in Cardiac Conduction and Their Rare Variants Identified in Sudden Unexplained Nocturnal Death Syndrome and Brugada Syndrome in Chinese Han Population

Association of common and rare variants of SCN10A gene with sudden unexplained nocturnal death syndrome in Chinese Han population

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