Analysis of mutations in EPOR, VHL, EPAS1 and EGLN1 genes associated with the familial erythrocytosis ECYT1-4 among JAK2- and CALR-negative patients with the erythrocytosis of unclear etiology

Abstract

Introduction. In addition to the clonal nature of the development of erythrocytosis, there are other causes, such as germinal mutations in genes of proteins responsible for the development of familial inherited erythrocytosis (EPOR, VHL, EPAS1, EGLN1, etc.).Aim. To conduct the analysis of mutations in the EPOR, VHL, EPAS1 and EGLN1 genes associated with the familial erythrocytosis ECYT1-4 among JAK2- and CALR-negative patients.Materials and methods. The study included 50 JAK2- and CALR-negative patients of Krasnoyarsk Krai with erythrocytosis of unclear etiology. Analysis of mutations in the EPOR, VHL, EPAS1 and EGLN1 genes, responsible for the development of familial erythrocytosis was conducted with the use of the Sanger sequencing. A mass parallel sequencing study was also performed for 12 patients.Results. The Sanger sequencing analysis of EPOR, VHL, EPAS1 and EGLN1 revealed any of the genetic variants in 22 of the 50 patients studied. Of all the variants identifi ed in the coding regions of the genes surveyed that result in amino acid substitutions, the following were of biggest interest: 1) two mutations in the VHL gene (rs28940298 and rs5030821) associated with the development of Chuvash polycythemia (ECYT2); 2) rs12097901 variant in the EGLN1 gene associated with altitude adaptation and increasing haemoglobin levels, but with no pathogenetic relevance for erythrocytosis according to ClinVar; and 3) one mutation in the EPOR gene not previously described in literature. According to the results of the NGS study, 12 somatic and 4 putative germinal variants were identifi ed in 5 out of 12 patients.Conclusion. The possibility of conducting a comprehensive molecular genetic study in order to identify new mutations or those already described in the literature in genes associated with familial erythrocytosis could make a signifi cant contribution to the diagnosis of patients with absolute erythrocytosis.