“Genetic Analysis of Inherited Cardiac diseases in Cypriot patients”

Abstract

Introduction: Cardiomyopathies are defined as disorders of the cardiac muscle and considered as the leading cause of sudden death in young athletes worldwide. The following study emphasizes on inherited cardiac diseases which are classified into cardiomyopathies and channelopathies, and there are several sub-categories based on the clinical and genetic phenotype. Inherited cardiomyopathies are divided into 4 subgroups: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC) and restrictive cardiomyopathy (RCM). The most common inherited channelopathies are divided into long QT syndrome (LQTS), short QT syndrome (SQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT) and Brugada syndrome. Objective: The main objective of the project was the genetic analysis of the DNA of probands with a suspicion of an inherited form of a cardiac disease, to identify genetic alterations that could be related to the probands’ clinical phenotype and identify the family members at risk. Methods: The genetic variations in probands’ DNA samples were identified through Next Generation Sequencing (NGS) using a panel of 72 genes related to cardiac diseases. The NGS results were validated through Sanger Sequencing. Once the proband was validated positive for a genetic variation, the testing was repeated for every family member with an available DNA sample. Once the validation of the results was completed, the pathogenicity of the genetic variants under study was evaluated in different databases (HGMD, ClinVar, Franklin, Varsome). Furthermore, bioinformatic algorithms were used to predict the pathogenicity at the cDNA level and protein level (Mutation taster, Polyphen-2, SIFT). Results: In this study, 11 families were examined with the panel of the 72 genes, and 25 genetic variations were identified, 20 of them novel. Most of the variants are responsible for probands clinicals phenotype although patterns of incomplete penetrance and co-inheritance of multiple genetic variants have been observed. Conclusions: Inherited cardiac diseases are characterized by genetic and phenotypic heterogeneity. The results indicate that in some cases these disorders may have oligogenic inheritance pattern, however further studies are required to verify it. Finally, To our knowledge, this is the first systematic study attempted in Cyprus for inherited cardiac conditions, enabling us to develop information about the genetic basis of these diseases and guidelines for new therapeutic approaches.