Prolonged Right Ventricular Ejection Delay in Brugada Syndrome Depends on the Type of &lt;i&gt;SCN5A&lt;/i&gt; Variant　― Electromechanical Coupling Through Tissue Velocity Imaging as a Bridge Between Genotyping and Phenotyping ―

Malderen, Sophie C H Van; Daneels, Dorien; Kerkhove, Dirk; Peeters, Uschi; Theuns, Dominic; Droogmans, Steven; Camp, Guy Van; Weytjens, Caroline; Biervliet, Martine; Bonduelle, M.; Dooren, Sonia Van; Brugada, Pedro

doi:10.1253/circj.cj-16-1279

Cited by 6 publications

(4 citation statements)

References 45 publications

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“…In population controls (gnomADv3.1.2), both the TTN and SCN5a variants have not been detected so far. However, the SCN5a variant has been described in Clinvar (NM_000335.5(SCN5A):c.1003T>C, p.Cys335Arg) in a patient with Brugada Syndrome and in one family with atrial fibrillation [ 10 , 11 ]. The SCN5a variant is a point mutation (1003T>C) that alters the amino acid at codon 335 from the cysteine (C) to arginine (R) located in the first transmembrane domain ( Figure 1 C).…”

Section: Resultsmentioning

confidence: 99%

“…While gain of function mutations lead to an increase of INa and thus longQT syndrome, loss of function mutations cause conduction disease, Brugada syndrome, or DCM [ 17 , 18 , 19 ]. SCN5a p.C335R was reported previously in association with arrhythmia; however, its pathogenicity was not well investigated [ 10 , 11 , 20 ]. In this study, we identified the SCN5a p.C335R variant in a very large family with DCM and conduction disease.…”

Section: Discussionmentioning

confidence: 99%

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Identification of SCN5a p.C335R Variant in a Large Family with Dilated Cardiomyopathy and Conduction Disease

Sedaghat‐Hamedani

Rebs

El‐Battrawy

et al. 2021

IJMS

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Introduction: Familial dilated cardiomyopathy (DCM) is clinically variable and has been associated with mutations in more than 50 genes. Rapid improvements in DNA sequencing have led to the identification of diverse rare variants with unknown significance (VUS), which underlines the importance of functional analyses. In this study, by investigating human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we evaluated the pathogenicity of the p.C335R sodium voltage-gated channel alpha subunit 5 (SCN5a) variant in a large family with familial DCM and conduction disease. Methods: A four-generation family with autosomal dominant familial DCM was investigated. Next-generation sequencing (NGS) was performed in all 16 family members. Clinical deep phenotyping, including endomyocardial biopsy, was performed. Skin biopsies from two patients and one healthy family member were used to generate human-induced pluripotent stem cells (iPSCs), which were then differentiated into cardiomyocytes. Patch-clamp analysis with Xenopus oocytes and iPSC-CMs were performed. Results: A SCN5a variant (c.1003T>C; p.C335R) could be detected in all family members with DCM or conduction disease. A novel truncating TTN variant (p.Ser24998LysfsTer28) could also be identified in two family members with DCM. Family members with the SCN5a variant (p.C335R) showed significantly longer PQ and QRS intervals and lower left ventricular ejection fractions (LV-EF). All four patients who received CRT-D were non-responders. Electrophysiological analysis with Xenopus oocytes showed a loss of function in SCN5a p.C335R. Na+ channel currents were also reduced in iPSC-CMs from DCM patients. Furthermore, iPSC-CM with compound heterozygosity (SCN5a p.C335R and TTNtv) showed significant dysregulation of sarcomere structures, which may be contributed to the severity of the disease and earlier onset of DCM. Conclusion: The SCN5a p.C335R variant is causing a loss of function of peak INa in patients with DCM and cardiac conduction disease. The co-existence of genetic variants in channels and structural genes (e.g., SCN5a p.C335R and TTNtv) increases the severity of the DCM phenotype.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of SCN5a p.C335R Variant in a Large Family with Dilated Cardiomyopathy and Conduction Disease

Sedaghat‐Hamedani

Rebs

El‐Battrawy

et al. 2021

IJMS

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“…Several studies compared the echocardiographic characteristics of patients with BrS and healthy individuals. On one hand, there are studies that support the absence of structural alterations in patients with BrS [ 12 ]. On the other hand, it was found that BrS patients showed an increase in right ventricular size, especially in the outflow tract diameter (RVOT) and telediastolic (RVED) and telesystolic (RVES) volumes with statistically significant impact [ 12 , 13 , 14 ].…”

Section: Cardiac Imaging In Brs Patientsmentioning

confidence: 99%

“…On one hand, there are studies that support the absence of structural alterations in patients with BrS [ 12 ]. On the other hand, it was found that BrS patients showed an increase in right ventricular size, especially in the outflow tract diameter (RVOT) and telediastolic (RVED) and telesystolic (RVES) volumes with statistically significant impact [ 12 , 13 , 14 ]. In order to exclude overlap syndromes between BrS and cardiomyopathies such as arrhythmogenic right ventricular cardiomyopathy (ARVC), some studies analyzed BrS and ARVC patients.…”

Section: Cardiac Imaging In Brs Patientsmentioning

confidence: 99%

Structural Abnormalities in Brugada Syndrome and Non-Invasive Cardiac Imaging: A Systematic Review

Raffele

Domenico

Balla

et al. 2023

Biology

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The aim of this review is to identify possible structural abnormalities of BrS and their potential association with symptoms, risk stratification, and prognosis. (1) Background: BrS has always been considered a purely electrical disease and imaging techniques do not currently play a specific role in the diagnosis of this arrhythmic syndrome. Some authors have recently hypothesized the presence of structural and functional abnormalities. Therefore, several studies investigated the presence of pathological features in echocardiography and cardiac magnetic resonance imaging (MRI) in patients with BrS, but results were controversial. (2) Methods: We performed a systematic review of the literature on the spectrum of features detected by echocardiography and cardiac MRI. Articles were searched in Pubmed, Cochrane Library, and Biomed Central. Only papers published in English and in peer-reviewed journals up to November 2021 were selected. After an initial evaluation, 596 records were screened; the literature search identified 19 relevant articles. (3) Results: The imaging findings associated with BrS were as follows: right ventricular dilation, right ventricular wall motion abnormalities, delayed right ventricular contraction, speckle and feature tracking abnormalities, late gadolinium enhancement, and fat infiltration in the right ventricle. Furthermore, these features emerged more frequently in patients carrying the genetic mutation on the sodium voltage-gated channel α-subunit 5 (SCN5A) gene. (4) Conclusions: Specific imaging features detected by echocardiography and cardiac magnetic resonance are associated with BrS. However, this population appears to be heterogeneous and imaging anomalies emerged to be more frequent in patients carrying genetic mutations of SCN5A. Future studies with an evaluation of BrS patients are needed to identify the specific association linking the Brugada pattern, imaging abnormalities and their possible correlation with prognosis.

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Case report: Synergetic effect of ischaemia and increased vagal tone inducing ventricular fibrillation in a patient with Brugada syndrome

Malderen

Schultz

Jordaens

2020

European Heart Journal - Case Reports

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Background Brugada syndrome (BS) is a hereditary channelopathy associated with syncope, malignant ventricular arrhythmia, and sudden cardiac death. Right ventricular ischaemia and BS have similar underlying substrates precipitating ventricular tachycardia or fibrillation (VF). Case summary A 72-year-old woman with BS and a stenosis on the proximal right coronary artery received several subsequent implantable cardioverter-defibrillator shocks due to VF during an episode of extreme nausea with vomiting. Discussion This case report emphasizes on the synergetic effect of mild ischaemia and increased vagal tone on the substrate responsible for BS to create pathophysiological changes precipitating VF.

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Prolonged Right Ventricular Ejection Delay in Brugada Syndrome Depends on the Type of <i>SCN5A</i> Variant　― Electromechanical Coupling Through Tissue Velocity Imaging as a Bridge Between Genotyping and Phenotyping ―

Abstract: Using the simple, non-invasive echocardiographic parameter RVED revealed a more pronounced 'electromechanical' delay in BrS patients carrying T variants ofSCN5A.

Cited by 6 publications

References 45 publications

Identification of SCN5a p.C335R Variant in a Large Family with Dilated Cardiomyopathy and Conduction Disease

Identification of SCN5a p.C335R Variant in a Large Family with Dilated Cardiomyopathy and Conduction Disease

Structural Abnormalities in Brugada Syndrome and Non-Invasive Cardiac Imaging: A Systematic Review

Case report: Synergetic effect of ischaemia and increased vagal tone inducing ventricular fibrillation in a patient with Brugada syndrome

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Prolonged Right Ventricular Ejection Delay in Brugada Syndrome Depends on the Type of <i>SCN5A</i> Variant ― Electromechanical Coupling Through Tissue Velocity Imaging as a Bridge Between Genotyping and Phenotyping ―

Abstract: Using the simple, non-invasive echocardiographic parameter RVED revealed a more pronounced 'electromechanical' delay in BrS patients carrying T variants ofSCN5A.

Cited by 6 publications

References 45 publications

Identification of SCN5a p.C335R Variant in a Large Family with Dilated Cardiomyopathy and Conduction Disease

Identification of SCN5a p.C335R Variant in a Large Family with Dilated Cardiomyopathy and Conduction Disease

Structural Abnormalities in Brugada Syndrome and Non-Invasive Cardiac Imaging: A Systematic Review

Case report: Synergetic effect of ischaemia and increased vagal tone inducing ventricular fibrillation in a patient with Brugada syndrome

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Prolonged Right Ventricular Ejection Delay in Brugada Syndrome Depends on the Type of <i>SCN5A</i> Variant　― Electromechanical Coupling Through Tissue Velocity Imaging as a Bridge Between Genotyping and Phenotyping ―