Long-term prognosis of patients with an SCN5A loss-of-function variant and progressive cardiac conduction disorder or Brugada syndrome.

Background: The long-term prognosis of patients with a loss-of-function variant in the cardiac sodium channel gene SCN5A is unknown.

Objective: This study aimed to evaluate the long-term arrhythmic risk in patients with an SCN5A loss-of-function variant to identify predictors of arrhythmic events.

Methods: Probands and family members with (likely) pathogenic SCN5A loss-of-function variants were retrospectively included.

Isolated prolapse of the posterior mitral valve leaflet: phenotypic refinement, heritability and genetic etiology.

Background: Isolated posterior leaflet mitral valve prolapse (PostMVP), a common form of MVP, often referred as fibroelastic deficiency, is considered a degenerative disease. PostMVP patients are usually asymptomatic and often undiagnosed until chordal rupture. The present study aims to characterize familial PostMVP phenotype and familial recurrence, its genetic background, and the pathophysiological processes involved.

Generation of a patient-specific induced pluripotent stem cell line carrying the DES p.R406W mutation, an isogenic control and a DES p.R406W knock-in line.

Mutations in the DES gene, which encodes the intermediate filament desmin, lead to desminopathy, a rare disease characterized by skeletal muscle weakness and different forms of cardiomyopathies associated with cardiac conduction defects and arrhythmias. We generated human induced pluripotent stem cells (hiPSC) from a patient carrying the DES p.R406W mutation, and employed CRISPR/Cas9 to rectify the mutation in the patient's hiPSC line and introduced the mutation in an hiPSC line from a control individual unrelated to the patient.

Filamin A heart valve disease as a genetic cause of inherited bicuspid and tricuspid aortic valve disease.

Objective: Variants in the gene have been associated with mitral valve dystrophy (MVD), and even polyvalvular disease has been reported. This study aimed to analyse the aortic valve and root involvement in -MVD families and its impact on outcomes.

Methods: 262 subjects (37 (18-53) years, 140 male, 79 carriers: +) from 4 -MVD families were included.

Type 3 long QT syndrome: Is the effectiveness of treatment with beta-blockers population-specific?

Background: The efficacy of beta-blocker treatment in type 3 long QT syndrome (LQT3) remains debated.

Objectives: The purpose of this study was to test the hypothesis that beta-blocker use is associated with cardiac events (CEs) in a French cohort of LQT3 patients.

Methods: All patients with a likely pathogenic/pathogenic variant in the SCN5A gene (linked to LQT3) were included and followed-up.

Functional Epicardial Conduction Disturbances Due to a SCN5A Variant Associated With Brugada Syndrome.

Background: Brugada syndrome is a significant cause of sudden cardiac death (SCD), but the underlying mechanisms remain hypothetical.

Objectives: This study aimed to elucidate this knowledge gap through detailed ex vivo human heart studies.

Methods: A heart was obtained from a 15-year-old adolescent boy with normal electrocardiogram who experienced SCD.

A need for exhaustive and standardized characterization of ion channels activity. The case of K11.1.

hERG, the pore-forming subunit of the rapid component of the delayed rectifier K current, plays a key role in ventricular repolarization. Mutations in the gene encoding hERG are associated with several cardiac rhythmic disorders, mainly the Long QT syndrome (LQTS) characterized by prolonged ventricular repolarization, leading to ventricular tachyarrhythmias, sometimes progressing to ventricular fibrillation and sudden death. Over the past few years, the emergence of next-generation sequencing has revealed an increasing number of genetic variants including variants.

Burden of rare variants in arrhythmogenic cardiomyopathy with right dominant form-associated genes provides new insights for molecular diagnosis and clinical management.

Arrhythmogenic cardiomyopathy with right dominant form (ACR) is a rare heritable cardiac cardiomyopathy disorder associated with sudden cardiac death. Pathogenic variants (PVs) in desmosomal genes have been causally related to ACR in 40% of cases. Other genes encoding nondesmosomal proteins have been described in ACR, but their contribution in this pathology is still debated.

A standardised hERG phenotyping pipeline to evaluate KCNH2 genetic variant pathogenicity.

Background And Aims: Mutations in KCNH2 cause long or short QT syndromes (LQTS or SQTS) predisposing to life-threatening arrhythmias. Over 1000 hERG variants have been described by clinicians, but most remain to be characterised. The objective is to standardise and accelerate the phenotyping process to contribute to clinician diagnosis and patient counselling.

Robustness and relevance of predictive score in sudden cardiac death for patients with Brugada syndrome.

Aims: Risk stratification of sudden cardiac arrest (SCA) in Brugada syndrome (Brs) remains the main challenge for physicians. Several scores have been suggested to improve risk stratification but never replicated. We aim to investigate the accuracy of the Brs risk scores.

Mutation Type and a Genetic Risk Score Associate Variably With Brugada Syndrome Phenotype in Families.

Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K- is the most common mutation identified.

Familial screening in case of acute myocarditis reveals inherited arrhythmogenic left ventricular cardiomyopathies.

Aims: Several data suggest that acute myocarditis could be related to genetic variants involved in familial cardiomyopathies, particularly arrhythmogenic cardiomyopathy, but the management of patients with acute myocarditis and their families regarding their risk for having an associated inherited cardiomyopathy is unclear.

Methods And Results: Families with at least one individual with a documented episode of acute myocarditis and at least one individual with a cardiomyopathy or a history of sudden death were included in the study. Comprehensive pedigree, including genetic testing, and history of these families were analysed.

Age at diagnosis of Brugada syndrome: Influence on clinical characteristics and risk of arrhythmia.

Background: Despite a strong genetic background, Brugada syndrome (BrS) mainly affects middle-age patients. Data are scarce in the youngest and oldest age groups.

Objective: The purpose of this study was to describe the clinical characteristics and variations in rhythmic risk in BrS patients according to age.

Number of electrocardiogram leads in the diagnosis of spontaneous Brugada syndrome.

Background: The recently recommended single lead-based criterion for the diagnosis of Brugada syndrome may lead to overdiagnosis of this disorder and overestimation of the risk of sudden cardiac death.

Aim: To investigate the value of a single-lead diagnosis in patients with Brugada syndrome and a spontaneous type 1 electrocardiogram.

Methods: Consecutive patients with Brugada syndrome were included in a multicentre prospective registry; only those with a spontaneous type 1 electrocardiogram were enrolled.

Clinical presentation and follow-up of women affected by Brugada syndrome.

Background: Studies in Brugada syndrome (BrS) have mainly consisted of men.

Objective: The purpose of this study was to describe the clinical characteristics and arrhythmic risk factors in BrS women.

Methods: Consecutive BrS patients were enrolled from 1993 and followed prospectively.

SCN5A mutations in 442 neonates and children: genotype-phenotype correlation and identification of higher-risk subgroups.

Aims: To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification.

Methods And Results: A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis.

Mental stress test: a rapid, simple, and efficient test to unmask long QT syndrome.

Aims: QT prolongation during mental stress test (MST) has been associated with familial idiopathic ventricular fibrillation. In long QT syndrome (LQTS), up to 30% of mutation carriers have normal QT duration. Our aim was to assess the QT response during MST, and its accuracy in the diagnosis of concealed LQTS.

New insights into mitral valve dystrophy: a Filamin-A genotype-phenotype and outcome study.

Aims: Filamin-A (FLNA) was identified as the first gene of non-syndromic mitral valve dystrophy (FLNA-MVD). We aimed to assess the phenotype of FLNA-MVD and its impact on prognosis.

Methods And Results: We investigated the disease in 246 subjects (72 mutated) from four FLNA-MVD families harbouring three different FLNA mutations.

Clinical Yield of Familial Screening After Sudden Death in Young Subjects: The French Experience.

Background: After sudden cardiac death with negative autopsy, clinical screening of relatives identifies a high proportion of inherited arrhythmia syndrome. However, the efficacy of this screening in families not selected by autopsy has never been assessed. We aim to investigate the value of clinical screening in relatives of all subjects who died suddenly before 45 years of age.

Value of the sodium-channel blocker challenge in Brugada syndrome.

Aims: Intravenous drug challenge is frequently performed to unmask Brugada syndrome (BrS). However, its true sensitivity has never been assessed. We used the obligate BrS transmitters in families affected by BrS to evaluate the true accuracy of drug challenge.

Sodium-channel blocker challenge in the familial screening of Brugada syndrome: Safety and predictors of positivity.

Background: Sodium-channel blocker challenge (SCBC) is frequently performed to unmask Brugada syndrome.

Objective: We aim to identify predictors of positivity and complications of SCBC in the setting of familial screening of Brugada syndrome.

Methods: All consecutive patients from 2000 to 2014 who benefit from a sodium-channel blocker and belong to a family with at least 2 subjects affected by the syndrome were enrolled and followed prospectively.