Recommendations for the Use of Genetic Testing in the Clinical Evaluation of Inherited Cardiac Arrhythmias Associated with Sudden Cardiac Death: Canadian Cardiovascular Society/Canadian Heart Rhythm Society Joint Position Paper (original) (raw)
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Canadian Journal of …, 2011
The era of gene discovery and molecular medicine has had a significant impact on clinical practice. Knowledge of specific genetic findings causative for or associated with human disease may enhance diagnostic accuracy and influence treatment decisions. In cardiovascular disease, gene discovery for inherited arrhythmia RÉSUMÉ L'ère de la découverte génétique et de la médecine moléculaire a eu un impact significatif dans la pratique clinique. La connaissance des découvertes génétiques spécifiques causales ou reliées à la maladie humaine peut améliorer la précision diagnostique et influencer les décisions de traitement. Dans la maladie cardiovasculaire, la découverte géné
EMQN: Recommendations for genetic testing in inherited cardiomyopathies and arrhythmias
European Journal of Human Genetics, 2023
Inherited cardiomyopathies and arrhythmias (ICAs) are a prevalent and clinically heterogeneous group of genetic disorders that are associated with increased risk of sudden cardiac death and heart failure. Making a genetic diagnosis can inform the management of patients and their at-risk relatives and, as such, molecular genetic testing is now considered an integral component of the clinical care pathway. However, ICAs are characterised by high genetic and allelic heterogeneity, incomplete / age-related penetrance, and variable expressivity. Therefore, despite our improved understanding of the genetic basis of these conditions, and significant technological advances over the past two decades, identifying and recognising the causative genotype remains challenging. As clinical genetic testing for ICAs becomes more widely available, it is increasingly important for clinical laboratories to consolidate existing knowledge and experience to inform and improve future practice. These recommendations have been compiled to help clinical laboratories navigate the challenges of ICAs and thereby facilitate best practice and consistency in genetic test provision for this group of disorders. General recommendations on internal and external quality control, referral, analysis, result interpretation, and reporting are described. Also included are appendices that provide specific information pertinent to genetic testing for hypertrophic, dilated, and arrhythmogenic right ventricular cardiomyopathies, long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia.
Frontiers in Cardiovascular Medicine, 2016
Advances in DNA sequencing have made large, diagnostic gene panels affordable and efficient. Broad adoption of such panels has begun to deliver on the promises of personalized medicine, but has also brought new challenges such as the presence of unexpected results, or results of uncertain clinical significance. Genetic analysis of inherited cardiac conditions is particularly challenging due to the extensive genetic heterogeneity underlying cardiac phenotypes, and the overlapping, variable, and incompletely penetrant nature of their clinical presentations. The design of effective diagnostic tests and the effective use of the results depend on a clear understanding of the relationship between each gene and each considered condition. To address these issues, we developed simple, systematic approaches to three fundamental challenges: (1) evaluating the strength of the evidence suggesting that a particular condition is caused by pathogenic variants in a particular gene, (2) evaluating whether unusual genotype/phenotype observations represent a plausible expansion of clinical phenotype associated with a gene, and (3) establishing a molecular diagnostic strategy to capture overlapping clinical presentations. These approaches focus on the systematic evaluation of the pathogenicity of variants identified in clinically affected individuals, and the natural history of disease in those individuals. Here, we applied these approaches to the evaluation of more than 100 genes reported to be associated with inherited cardiomyopathies and arrhythmias including hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular dysplasia or cardiomyopathy, long QT syndrome, short QT syndrome, Brugada, and catecholaminergic polymorphic ventricular tachycardia, and to a set of related syndromes such as Noonan Syndrome and Fabry disease. These approaches provide a framework for delivering meaningful and accurate genetic test results to individuals with hereditary cardiac conditions.
Yield of Molecular and Clinical Testing for Arrhythmia Syndromes
Circulation, 2013
Background— Sudden cardiac death is often caused by inherited arrhythmia syndromes, particularly if it occurs at a young age. In 1996, we started a cardiogenetics clinic aimed at diagnosing such syndromes and providing timely (often presymptomatic) treatment to families in which such syndromes or sudden cardiac death existed. We studied the yield of DNA testing for these syndromes using a candidate-gene approach over our 15 years of experience. Methods and Results— We analyzed the yield of DNA testing. In subanalyses, we studied differences in the yield of DNA testing over time, between probands with isolated or familial cases and between probands with or without clear disease-specific clinical characteristics. In cases of sudden unexplained death (antemortem or postmortem analysis of the deceased not performed or providing no diagnosis), we analyzed the yield of cardiological investigations. Among 7021 individuals who were counseled, 6944 from 2298 different families (aged 41±19 ye...
Clinical Impact of Genetic Studies in Lethal Inherited Cardiac Arrhythmias
Circulation Journal, 2008
Over the past decade, molecular genetic studies have established a link between a number of inherited cardiac arrhythmias, including congenital long QT syndrome (LQTS) and Brugada syndrome (BrS), and mutations in genes encoding for ion channels or other membrane components. Twelve forms of LQTS have been identified in 50-70% of clinically affected patients. Genotype-phenotype correlations have been rigorously investigated in LQT1, LQT2 and LQT3 syndromes, which constitute more than 90% of genotyped LQTS patients, enabling stratification of risk and effective treatment of genotyped patients. Genotype-specific triggers for both the cardiac events and the clinical course have been reported, and genotype-specific therapy has been already introduced. More recently, mutation site-specific differences in the clinical phenotype have been reported in LQT1 and LQT2 patients, indicating the possibility of mutation site-specific management or treatment. In contrast, only one-third of BrS patients can be genotyped, and data on genotype-phenotype relationships in clinical studies are limited. A Haplotype B consisting of 6 individual DNA polymorphisms within the proximal promoter region of the SCN5A gene was recently identified only in Asians (frequency 22%). Individuals with Haplotype B show significantly longer duration of both PQ and QRS than those without Haplotype B, indicating that Haplotype B likely contributes to the higher incidence of BrS in Asian populations.
Clinical and genetic diagnosis for inherited cardiac arrhythmias
Journal of Nippon Medical School = Nippon Ika Daigaku zasshi, 2014
Molecular genetic studies in the last 2 decades have revealed a link between several inherited cardiac arrhythmias and genes encoding for ion channels or other membrane components. Two recent international expert consensus statements endorsed by 3 continental electrophysiology societies have updated the clinical and genetic diagnoses and management in patients with inherited arrhythmia syndromes, including congenital long QT syndrome (LQTS) and Brugada syndrome. Thirteen genotypes have been identified in 50% to 80% of clinically affected patients with congenital LQTS. Therefore, genotype-phenotype correlations have been investigated, especially, in the 3 major genotypes--LQT1, LQT2 and LQT3 syndromes--enabling genotype-specific management and therapy. On the other hand, less than half of patients with Brugada syndrome can be genotyped, and mainly for the sodium channel gene, SCN5A. However, recent advances in molecular genetic testing include genome-wide association studies using ge...
Emerging Implications of Genetic Testing in Inherited Primary Arrhythmia Syndromes
Cardiology in Review
Inherited primary arrhythmia syndromes are genetically determined disorders of cardiac ion channels or ion channel macromolecular complexes usually associated with a higher risk of sudden cardiac death. These conditions have a very broad spectrum of clinical manifestations, ranging from an asymptomatic course to syncope, atrial and ventricular arrhythmias, and conduction disturbances, but may produce sudden infant death syndrome and unexplained sudden cardiac death in apparently healthy individuals. During the last 20 years, the evolving knowledge on the genetic basis of inherited arrhythmia syndromes has dramatically reshaped our understanding of these conditions and, consequently, had a great impact on patient care. Based on the knowledge of the genetic substrates, specific risk factors for individual genotypes have been identified, and various investigations have been launched with the intention of developing a gene-and even mutation-specific therapy. Preliminary results from animal studies suggest that gene therapy rescues the normal ion channel function and thereby prevents cardiac events in some primary arrhythmia syndromes, which suggests that upon appropriate validation in a clinical setting, it may become available for affected patients. The purpose of this review is to provide clinicians with a contemporary insight into the role of genetic testing in the diagnosis, therapy, and prognosis of patients with primary arrhythmia syndromes, and the clinical implications of screening family members who are at risk of sudden cardiac death.