Application of next generation sequencing in cardiology: current and future precision medicine implications.

Inherited cardiovascular diseases are highly heterogeneous conditions with multiple genetic loci involved. The application of advanced molecular tools, such as Next Generation Sequencing, has facilitated the genetic analysis of these disorders. Accurate analysis and variant identification are required to maximize the quality of the sequencing data. Therefore, the application of NGS for clinical purposes should be limited to laboratories with a high level of technological expertise and resources. In addition, appropriate gene selection and variant interpretation can result in the highest possible diagnostic yield. Implementation of genetics in cardiology is imperative for the accurate diagnosis, prognosis and management of several inherited disorders and could eventually lead to the realization of precision medicine in this field. However, genetic testing should also be accompanied by an appropriate genetic counseling procedure that clarifies the significance of the genetic analysis results for the proband and his family. In this regard, a multidisciplinary collaboration among physicians, geneticists, and bioinformaticians is imperative. In the present review, we address the current state of knowledge regarding genetic analysis strategies employed in the field of cardiogenetics. Variant interpretation and reporting guidelines are explored. Additionally, gene selection procedures are accessed, with a particular emphasis on information concerning gene-disease associations collected from international alliances such as the Gene Curation Coalition (GenCC). In this context, a novel approach to gene categorization is proposed. Moreover, a sub-analysis is conducted on the 1,502,769 variation records with submitted interpretations in the Clinical Variation (ClinVar) database, focusing on cardiology-related genes. Finally, the most recent information on genetic analysis's clinical utility is reviewed.

Atrial fibrillation in hypertrophic cardiomyopathy - A contemporary mini-review.

Hypertrophic cardiomyopathy (HCM) represents the most common genetically inherited cardiovascular disorder and a leading cause of heart failure and sudden cardiac death. Atrial fibrillation (AF) is the most common arrhythmia encountered in HCM patients, primarily due to the process of left atrium dilatation and remodeling. Its presence typically leads to progressive functional decline, increased frequency of heart failure hospitalizations, and increased thromboembolic risk. In this mini-review, we summarize the contemporary data on AF pathophysiology, risk factors, and management in HCM patients suffering from AF.

Current perspectives on the diagnosis and management of dilated cardiomyopathy Beyond heart failure: a Cardiomyopathy Clinic Doctor's point of view.

Left ventricular enlargement and dysfunction are fundamental components of dilated cardiomyopathy (DCM). DCM is a major cause of heart failure and cardiac transplantation. A wide variety of etiologies underlie acquired and familial DCM. Familial disease is reported in 20% to 35% of cases. A genetic substrate is recognized in at least 30% of familial cases. A recently proposed scheme defines DCM as a continuum of subclinical and clinical phenotypes. The evolution of classification systems permitted use of effective treatment strategies in disorders sharing the same structural and functional characteristics and common clinical expression. The major causes of death are progressive heart failure and sudden cardiac death secondary to ventricular arrhythmias or less commonly bradyarrhythmias. Remarkable progress has been made in survival owing to well-defined evidence-based therapies and appropriate guidelines for risk stratification and sudden cardiac death prevention measures. Neurohormonal antagonists and device therapy decreased all-cause mortality in adult patients with DCM. However, additional red flags in diagnosis have to be addressed in everyday practice, and cardiologists have to be aware of the subsequent effect on risk stratification and treatment plan. Genetic substrate cannot be modified, but the presence of a peculiar type of gene mutation modifies thresholds for implantable cardioverter defibrillator (ICD) implantation. DCM is part of the spectrum of heart failure which is a syndrome with certain morphological and functional characteristics. Although significant progress has been achieved in the management of patients with DCM, it seems that the future treatments of this entity will be related to the specific pathological substrate.

Sudden unexplained death in the young: epidemiology, aetiology and value of the clinically guided genetic screening.

Aims: To determine the incidence and the causes of sudden death (SD) in persons aged 1-35 years old and the diagnostic yield of clinically guided genetic screening in the sudden arrhythmic death syndrome (SADS) victims' families. Methods and results: Incidence and causes of SD in the Attica region of Greece in 2002-10 were determined using death certificates and autopsy reports. We evaluated clinically consecutive families of SADS victims and if a clinical diagnosis was established, we proceeded to targeted genetic analysis. Out of 6030 deaths, 56% were due to traumatic or violent causes, 40.5% were natural deaths, and 3.3% were of undetermined cause. There were 349 SD cases. Cardiovascular causes accounted for 65%, non-cardiovascular causes for 17%, and SADS for 18%. Clinical evaluation identified an inherited heart disease in 5/20 SADS families (25%). Targeted genetic analysis identified a causative mutation in all of the five screened families and reconfirmed the diagnosis in three of five proband victims. Clinical and genetic evaluation of 28 family members identified eight affected carriers and eight non-affected carriers. Molecular autopsy failed to identify any of these families. Conclusion: Sudden death in the young is of cardiovascular origin in the majority of cases. A considerable rate of SD cases remains of unknown cause on post-mortem. Apart from channelopathies, subclinical forms of inherited structural heart diseases would appear to be implicated in SADS. Clinically guided genetic screening has a significant diagnostic yield and identifies affected families that would have been missed by the current suggested molecular autopsy panel.