Cпектр мутаций в генах саркомерных белков и их фенотипическое проявление у белорусских пациентов с гипертрофической кардиомиопатией

Background. Hypertrophic cardiomyopathy (HCM) is a hereditary pathology, the main cause of which is mutations in the genes encoding the protein components of the myofibril apparatus of cardiomyocytes, and the spectrum of these genetic changes has population features. The aim of the study was to determine the spectrum of mutations in the genes encoding sarcomeric proteins in patients with HCM from Belarus, as well as to study the association between the genotype and the phenotypic manifestations of the disease. Materials and methods. The study included 340 unrelated patients with HCM from Belarus. Mutation detection in the coding sequences of ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNI3, TNNT2, TNNС1 и TPM1 genes was performed by next generation sequencing (NGS) in 89 patients. The directed search for genetic defects detected by the NGS method was carried out by the automatic sequencing method using Sanger and PCR-RFLP analysis. Results. The NGS method allowed to detect mutations in the genes of 51,7% of patients: MYBPC3 (20,2%), MYH7 (16,9%), TPM1 (3,4%), ACTC1 (2,3%), MYL2 (1,1 %) and TNNC1 (1,1%). In 6,7% of individuals two (5,6%) or three (1,1%) substitutions were observed. New mutations were found: p.Ala49Asn, p.Val1407Phe in the MYH7 gene; p.Tyr501Ser, p.Trp1007fs, p.Tyr1043*, p.Pro1066Arg, p.Arg1138fs, p.Pro1181Gln, р.Cys1202Arg in the MYBPC3 gene. The most frequently occurring mutations were identified: p.Gln1233*, p.Ser871Alafs, the combination of the р.Glu1265Val + p.Cys1266Arg, R.Gln401*, and Trp1214Arg in the MYBPC3 gene, p.Glu924Lys and p.Glu1356Lys in the MYH7 gene. According to the ECG study, carriers of mutations in sarcomere protein genes, especially with missense mutations in the MYBPC3 gene, had more severe myocardial hypertrophy and early disease manifestation then patients without mutations in those genes. The p.Gln1233* mutation was the most common among Belarusian patients and characterized by late onset of the disease, mild left ventricular myocardial hypertrophy and the more frequent development of atrial fibrillation. Conclusions. In general, the distribution of mutations in the genes encoding sarcomeric proteins in patients with HCM from Belarus didn’t differ from other European populations. 84,9% of the detected mutations were localized in MYBPC3 and MYH7 genes.