Abstract
JAK2-unmutated erythrocytosis or non-polycythemia vera erythrocytosis is a rare condition comprising both acquired and hereditary forms. Although acquired erythrocytosis has been well-studied, hereditary erythrocytosis remains poorly studied. Genetic alterations associated with hereditary erythrocytosis include mutations in erythropoietin receptor and erythropoietin (EPO), altered oxygen affinity mutations, and variants associated with the oxygen-sensing pathway. We established a molecular diagnostic approach based on these genes and retrospectively evaluated. Peripheral blood from 56 erythrocytosis patients, lacking JAK2 mutation, were screened for oxygen-sensing pathway abnormalities. Two novel mutations were identified in the EGLN1 gene: NM_022051.2:c.712G > C (p.Gly238Arg) and NM_022051.2:c.122A > C (p.Tyr41Ser) in two patients separately. Notably, both reported heterozygous mutations were absent in the population database. Predictions using multiple computer software indicated that these two missense mutations were harmful and induced a highly conserved amino acid change in EGLN1. Patients with the two mutations exhibited normal serum EPO levels and high hemoglobin and hematocrit levels. Additionally, three other variants of genes were identified in the oxygen-sensing pathway, including endothelial PAS domain protein 1 (EPAS1) rs184760160(2/56), and EGLN1 rs186996510(2/56), rs555121182(2/56). These variants were categorized as benign or likely benign. Our findings provide a framework for etiological research and highlight the importance of screening for genetic mutations associated with erythrocytosis in clinical practice.
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This research was funded by Beijing Natural Science Foundation, grant number Z200022; Capital’s Funds for Health Improvement and Research (CFH), Grant number 2022-2-2019.
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Conceptualization, WH, RH and QM; methodology, QM and YL; validation, QM; formal analysis, QM and WH; resources, RH, DZ, HZ; writing—original draft preparation, QM; writing—review and editing, QM, RH, WS; supervision, WS; funding acquisition, WS and RH. All authors have read and agreed to the published version of the manuscript.
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The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Ethics Committee of Xuanwu Hospital, Capital Medical University (protocol code [2022]013 and May 29, 2023).
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Ma, Q., Hu, R., Hui, W. et al. Two Novel Genetic Variants Involved in the Oxygen Sensing Pathway in JAK2-unmutated Erythrocytosis. Biochem Genet (2024). https://doi.org/10.1007/s10528-024-10752-2
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DOI: https://doi.org/10.1007/s10528-024-10752-2