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.

JAK2-未突变红细胞增多症或非真性红细胞增多症是一种罕见疾病，包括获得性和遗传性两种形式。尽管获得性红细胞增多症已得到充分研究，但遗传性红细胞增多症的研究仍然很少。与遗传性红细胞增多症相关的基因改变包括促红细胞生成素受体和促红细胞生成素 ( EPO )突变、氧亲和力突变改变以及与氧感应通路相关的变异。我们建立了基于这些基因的分子诊断方法并进行回顾性评估。对 56 名缺乏JAK2突变的红细胞增多症患者的外周血进行了氧传感通路异常筛查。两名患者的EGLN1基因中分别发现了两个新突变：NM_022051.2:c.712G > C (p.Gly238Arg) 和 NM_022051.2:c.122A > C (p.Tyr41Ser)。值得注意的是，人口数据库中不存在报告的两种杂合突变。使用多个计算机软件的预测表明，这两个错义突变是有害的，并诱导EGLN1中高度保守的氨基酸变化。携带这两种突变的患者表现出正常的血清 EPO 水平以及高血红蛋白和红细胞比容水平。此外，在氧传感通路中还发现了其他三个基因变体，包括内皮PAS结构域蛋白1（EPAS1）rs184760160（2/56）和EGLN1 rs186996510（2/56）、rs555121182（2/56）。这些变异被归类为良性或可能良性。我们的研究结果为病因学研究提供了框架，并强调了在临床实践中筛查与红细胞增多症相关的基因突变的重要性。