Spectrum of non-pathogenic variants in the titin gene and genes outside and intra-carcomeric cytoskeleton (TTN, MYBPC3, FLNC, RBM20) in patients with various variants of cardiomyopathy

Background. Sarcomere protein genes such as MYBPC3, FLNC, TTN, RBM20 are associated with cardiomyopathies (CMP). A large number of rare genetic variants complicates the interpretation genetic studies and assessing the pathogenicity. Moreover, there is a lack of an information about rare variants frequency in a healthy Russian population. Polymorphisms in these genes often act as modifiers, aggravating the clinical course of CMP caused by mutations in other genes. Objective. To compare the frequency of rare (less than 0.1 %) missense and truncating variants in the TTN, FLNC, MYBPC3, RBM20 genes in the patients with CMP and in the general population. Design and methods. The CMP group included 251 patients. The control group included 192 men (from the ESSE-RF study). A molecular genetic examination was performed using high-processive sequencing technology, followed by verification by Sanger sequencing. Results. The frequency of truncating variants in the genes TTN, FLNC, MYBPC3, RBM20 in the group with CMP was 7.17 %, and missense variants — 56.6 %: 11.5 % were pathogenic/likely pathogenic, 39.5 % — variants of uncertain significance, 49 % — probably benign/benign. The frequency of truncating variants in the TTN, FLNC, MYBPC3, RBM20 genes in the control group was 0.52 %, and the frequency of missense variants was 15.1 %: 38 % were variants of uncertain significance, 62 % — probably benign/benign. Conclusion. Frequency of missense and truncating variants with a frequency of less than 0.1 % in the TTN, FLNC, MYBPC3, RBM20 genes was increased in the group of patients with CMP.