Storia naturale dei difetti di conduzione atrio-ventricolari e aritmie in pazienti con cardiomiopatia dilatativa : analisi genetica mediante next generation sequencing

NATURAL HISTORY OF ATRIOVENTRICULAR CONDUCTION DEFECTS AND ARRHITMIAS IN PATIENTS WITH DILATIVE CARDIOMYOPATHY: CLINICAL-PROGNOSTIC VALUE OF THE GENETIC ANALYSIS USING NEXT GENERATION SEQUENCING Background Dilated cardiomyopathy is one of the most common cardiomyopathies that at the onset shows a with dysfunction, commonly expressed by the reduced ejection fraction (EF) and which can lead to heart transplantation. Cardiac "laminopathies" are part of the complex set of CMD. In many cases they show a defect in myocardial electrical conduction. Mutations in the Lamina A / C genes have been associated with high arrhythmic risk and sudden cardiac death. In addition to these, there are others concerning the MYH7, TTN, MYBPC3 genes, related to the CMD phenotype and whose meaning is being defined. Objectives The project has the goal of evaluating the association of arrhythmic disorders with possible CMD phenotypes and the genetic mutations described above. Materials and Methods We studied 33 out of 100 patients screened for CMD on voluntary availability, suffering from different forms without significant coronary lesions. All of them underwent diagnostic-instrumental checks (ECG, Holter Ecg, echocardiogram and enzymatic profile) and followed for a minimum period of 18 months. At the same time at the ordinary check -up, genetic analyses were carried out through the NGS study of a panel of genes related to CMD in collaboration between the AOU G. Martino di Messina and the Bambino Gesu’ Hospital in Rome. Results On 33 patients undergoing a genetic study, variants of uncertain significance (VUS) were identified: variant c.2359 C> T (p.Arg787Cys) in the MYH7 gene reported in VarSome as probably pathogenetic in a symptomatic patient with endomyocardial biopsy CMD + ; the variant c.54016G> T in heterozygosity in the TTN gene, in another case, which at the protein level determines the introduction of the premature stop codon not described in scientific literature and classified according to the ACMG guidelines as a probably pathogenic variant; finally pathogenic variant c.949G> A in heterozygosity in the LMNA gene, in a family with a history of sudden cardiac death with manifest CMD in some members with arrhythmias at follow up (ICD). and the presence of a second mutation; c.836G> C in heterozygosity in the MYBPC3 gene, in other members of the same family with better clinical course. Conclusions Our study shows that there are VUS associated with cases of CMD. Within these, the presence of mutations in the lamina gene seem to be more closely related to the incidence of arrhythmias. Therefore, further studies are necessary for a better definition of all possible VUS also to carry out a differential diagnosis in the broad spectrum of cardiomyopathies.