Genetic Variation in Titin in Patients with Hypertrophic and Noncompaction Cardiomyopathy

NGS was used to determine the coding sequence of the TTN gene in patients with left ventricular noncompaction cardiomyopathy (LVNC, 44 individuals) and hypertrophic cardiomyopathy (HCM, 74 individuals), as well as in the control (194 individuals); nine titin-truncating variants (TTNtv) and 372 missense variants were identified. A comparative analysis of the genetic variability of titin between the groups of patients with LVNC and HCM and the control sample was carried out in terms of the type of mutations and their localization in the exons of genes, as well as in the sarcomeric and functional domains of the protein. The role of TTNtv in the development of LVNC was confirmed, and the significance of additional variants in the same or other genes associated with various cardiomyopathies for the phenotypic implementation of TTNtv was demonstrated. Seventy-five percent of patients with TTNtv had a dilated LVNC phenotype. Missense substitutions in the TTN gene were found both among the patients with LVNC and HCM, and in people in the control sample, which indirectly confirms that most missense variants in this gene are benign. The paper identifies and lists highly mutable and conserved exons of the TTN gene and also presents a list of missense mutations with possible clinical significance in relation to the structural pathology of the myocardium, including new variants. It was shown that the majority of pathogenic and potentially significant mutations were located in the A-band of the sarcomere. In all groups, about 30–50% of new variants were identified. Probably, many of them are neutral and are of exclusively population interest.