Features of the appearance of clinical cardiomyopathies against the background of truncating variants in the <i>ttn</i> gene: a review of the literature and an analysis of the appearance.

Abstract

Background. To date, the influence of genetic variants in the titin gene on the development of all types of cardiomyopathies has been proven, and this primarily applies to TTNtv, however, the high frequency of these variants in the control population (1–3 %) significantly complicates the determination of the pathogenicity of the detected variants. In addition, due to a significant population frequency (1–3 %) in patients with CMP, variants in the titin gene are often combined with causal variants in other genes, and thus can act as modifiers of the clinical course of the disease and myocardial remodeling.Objective. To study the effect of shortening variants in the titin gene on the clinical course of cardiomyopathies in the presence of causative variants in other genes or etiological factors of the disease.Design and methods. This article will consider three clinical cases of patients diagnosed with CMP who were treated at the Almazov National Medical Research Center. To conduct a genetic examination, next generation sequencing was used with a target cardiopanel to check 108 genes associated with the development of cardiomyopathies, as well as Sanger sequencing to exclude false positive results.Results. During a genetic examination of the studied patients, identified genetic variants in the titin gene led to the syn- thesis of a truncated protein: in all cases, the reason for this was frameshift deletions located in exons with a PSI (Percent Spliced-In) level of 100%. According to the American College of Medical Genetics and Genomics pathogenicity classification, two genetic variants are classified as pathogenic and one is classified as probably pathogenic.Conclusion. In these patients, we found shortening variants (frameshift deletions) in the titin gene, which acted as modifiers of myocardial remodeling.