Promise and Peril of a Genotype-First Approach to Mendelian Cardiovascular Disease.

Precision medicine, which among other aspects includes an individual's genomic data in diagnosis and management, has become the standard-of-care for Mendelian cardiovascular disease (CVD). However, early identification and management of asymptomatic patients with potentially lethal and manageable Mendelian CVD through screening, which is the promise of precision health, remains an unsolved challenge. The reduced costs of genomic sequencing have enabled the creation of biobanks containing in-depth genetic and health information, which have facilitated the understanding of genetic variation, penetrance, and expressivity, moving us closer to the genotype-first screening of asymptomatic individuals for Mendelian CVD.

[Pregnancy Management in a Patient with Long QT Syndrome Type 2 (LQT2) carrier of the variant KCNH2: Trp100X].

Long QT syndrome (LQTS) is a congenital ion channel disorder causing prolonged ventricular repolarization and presents on surface ECG with a prolonged QTc interval. This condition predisposes to ventricular arrhythmias and also sudden cardiac death. LQTS without appropriate therapy during pregnancy and the postnatal phase poses an additionally increased risk of sudden cardiac death due to physiological changes associated with gestation.

Catecholaminergic Polymorphic Ventricular Tachycardia: Multiple Clinical Presentations of a Genetically Determined Disease.

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare, inherited heart rhythm disorder that is caused by variants in genes responsible for cardiac calcium homeostasis. The aim of this study was to analyze different genotype-specific clinical manifestations of this disease.

Methods And Results: We analyzed five CPVT cases from our institution in the context of specific patient characteristics and genotype-phenotype correlations.

Genetics in Probands With Idiopathic Ventricular Fibrillation: A Multicenter Study.

Background: Different genes have been associated with idiopathic ventricular fibrillation (IVF); however, there are no studies correlating genotype with phenotype.

Objectives: The aim of this study was to define the genetic background of probands with IVF using large gene panel analysis and to correlate genetics with long-term clinical outcomes.

Methods: All consecutive probands with a diagnosis of IVF were included in a multicenter retrospective study.

Evolution and triggers of defibrillator shocks in patients with arrhythmogenic right ventricular cardiomyopathy.

Introduction: Implantable cardioverter-defibrillators (ICDs) can prevent sudden cardiac death due to ventricular arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). The aim of our study was to assess the cumulative burden, evolution and potential triggers of appropriate ICD shocks during long-term follow-up, which may help to reduce and further refine individual arrhythmic risk in this challenging disease.

Methods: This retrospective cohort study included 53 patients with definite ARVC according to the 2010 Task Force Criteria from the multicentre Swiss ARVC Registry with an implanted ICD for primary or secondary prevention.

A Novel Heterozygous Desmoplakin Variant Causes Cardiocutaneous Syndrome with Arrhythmogenic Cardiomyopathy and Palmoplantar Keratosis.

Cardiocutaneous syndrome (CCS) is often caused by genetic variants in desmoplakin () in the presence of thick calluses on the hands and soles of the feet (palmoplantar keratoderma) in combination with arrhythmogenic cardiomyopathy. In this case report, we describe a 58-year-old man presenting with a history of cardiomyopathy with recurrent sustained ventricular tachycardia and palmoplantar keratosis. The cardiological evaluation showed biventricular cardiomyopathy, and repeated genetic testing identified a novel variant.

Biventricular Arrhythmogenic Cardiomyopathy Associated with a Novel Heterozygous Early Truncating Variant.

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a hereditary condition that can cause sudden cardiac death in young, frequently athletic individuals under the age of 35 due to malignant arrhythmias. Competitive and endurance exercise may hasten the onset and progression of ARVC, leading to right ventricular dysfunction and potentially fatal ventricular arrhythmias earlier in life. In this article, we present a novel, pathogenic, early truncating heterozygous variant in the gene that causes biventricular arrhythmogenic cardiomyopathy and affects a family, of which the only member with the positive phenotype is a competitive endurance athlete.

Role of genetic testing in young patients with idiopathic atrioventricular conduction disease.

Aims: To investigate the role of genetic testing in patients with idiopathic atrioventricular conduction disease requiring pacemaker (PM) implantation before the age of 50 years.

Methods And Results: All consecutive PM implantations in Southern Switzerland between 2010 and 2019 were evaluated. Inclusion criteria were: (i) age at the time of PM implantation: < 50 years; (ii) atrioventricular block (AVB) of unknown aetiology.

Brugada Syndrome Associated with Different Heterozygous Variants in Two Unrelated Families.

The cardiac sodium channel (Nav1.5) controls cardiac excitability by triggering the action potential of cardiac myocytes and controlling electric impulse transmission. However, it has also been associated with arrhythmogenic cardiomyopathies.

Clinical Spectrum of Channelopathy in Children with Primary Electrical Disease and Structurally Normal Hearts.

Sodium voltage-gated channel α subunit 5 (-mutations may cause an array of arrhythmogenic syndromes most frequently as an autosomal dominant trait, with incomplete penetrance, variable expressivity and male predominance. In the present study, we retrospectively describe a group of Mexican patients with -disease causing variants in whom the onset of symptoms occurred in the pediatric age range. The study included 17 patients with clinical diagnosis of primary electrical disease, at least one pathogenic or likely pathogenic mutation and age of onset <18 years, and all available first- and second-degree relatives.

Filamin C missense variant associated with severe right atrial disease and skeletal myopathy.

Introduction: Filamin C (FLNC) gene variants associated with atrial cardiomyopathies have not been reported so far. The aim of this study was to assess the genetics of two siblings presenting with recurrent right atrial arrhythmias, severe right atrial dilatation, and skeletal myopathy.

Methods: A family with subjects affected by recurrent atrial arrhythmias and skeletal myopathy was extensively evaluated by the means of electrocardiographic recordings, magnetic resonance, intracardiac high-density mapping, and genetic testing.

The genetic architecture of Plakophilin 2 cardiomyopathy.

Purpose: The genetic architecture of Plakophilin 2 (PKP2) cardiomyopathy can inform our understanding of its variant pathogenicity and protein function.

Methods: We assess the gene-wide and regional association of truncating and missense variants in PKP2 with arrhythmogenic cardiomyopathy (ACM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) specifically. A discovery data set compares genetic testing requisitions to gnomAD.

Evidence-Based Assessment of Genes in Dilated Cardiomyopathy.

Background: Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture.

Sex-Related Differences in Cardiac Channelopathies: Implications for Clinical Practice.

Sex-related differences in prevalence, clinical presentation, and outcome of cardiac channelopathies are increasingly recognized, despite their autosomal transmission and hence equal genetic predisposition among sexes. In congenital long-QT syndrome, adult women carry a greater risk for Torsades de pointes and sudden cardiac death than do men. In contrast, Brugada syndrome is observed predominantly in adult men, with a considerably higher risk of arrhythmic sudden cardiac death in adult men than in women.

Familial Arrhythmogenic Cardiomyopathy: Clinical Determinants of Phenotype Discordance and the Impact of Endurance Sports.

Arrhythmogenic cardiomyopathy (ACM) is primarily a familial disease with autosomal dominant inheritance. Incomplete penetrance and variable expression are common, resulting in diverse clinical manifestations. Although recent studies on genotype-phenotype relationships have improved our understanding of the molecular mechanisms leading to the expression of the full-blown disease, the underlying genetic substrate and the clinical course of asymptomatic or oligo-symptomatic mutation carriers are still poorly understood.

Impact of Genetic Variant Reassessment on the Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy Based on the 2010 Task Force Criteria.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy, which is associated with life-threatening ventricular arrhythmias. Approximately 60% of patients carry a putative disease-causing genetic variant, but interpretation of genetic test results can be challenging. The aims of this study were to systematically reclassify genetic variants in patients with ARVC and to assess the impact on ARVC diagnosis.

Potential pro-arrhythmic effects of pharmacotherapy against SARS-CoV-2.

The pandemic caused by the SARS-COV-2 or COVID-19 virus has been a global challenge given its high rate of transmission and lack of effective therapy or vaccine. This scenario has led to the use of various drugs that have demonstrated a potential effect against the virus in vitro. However, time has not been enough to properly evaluate their clinical effectiveness.

Clinical predictors of left ventricular involvement in arrhythmogenic right ventricular cardiomyopathy.

Aim: The impact of clinical characteristics for predicting patterns of ventricular involvement in arrhythmogenic right ventricular cardiomyopathy (ARVC) are not well defined. The aims of this study were to characterize different patterns of ventricular involvement in patients with ARVC and to stratify them based on clinical characteristics exercise and underlying genetic mutations.

Methods: Sixty-four patients with definite ARVC from the Swiss ARVC Registry were enrolled.

Outcome of video-assisted thoracoscopic implantation of epicardial left ventricular leads with visual targeting for cardiac resynchronization therapy.

Objectives: Our goal was to analyse the implantation and outcome of thoracoscopic epicardial leads after a failed endovascular approach or follow-up (FU) complications after endovascular implantation.

Methods: We reviewed the records of patients with failed endovascular left ventricular (LV) lead placement or complications during FU, who were subsequently referred to cardiac surgeons for treatment with thoracoscopic LV lead implantation. We analysed the reasons for endovascular failure; the indications for the surgical procedures; and the clinical, echocardiographic and device FU results.