Genetic Basis of Congenital Erythrocytosis: Mutation Update and Online Databases

Abstract

Congenital Erythrocytosis (CE), also called congenital polycythemia, represents a rare and heterogeneous clinical entity. It is caused by deregulated red blood cell production where erythrocyte overproduction results in elevated hemoglobin and hematocrit levels. 3Primary congenital familial erythrocytosis is associated with low erythropoietin (Epo) levels and generally results from mutations in the erythropoietin-receptor gene (EPOR).Secondary congenital erythrocytosis arises from conditions which cause tissue hypoxia thus resulting in increased Epo production. These include hemoglobin variants with increased affinity for oxygen (genes HBB, HBA1 and HBA2), decreased production of 2,3-biphosphoglycerate due to mutations in the BPGM gene, or mutations in the genes involved in the hypoxia sensing pathway (VHL, EPAS1 and EGLN1). Depending on the affected gene CE can be inherited either in an autosomal dominant or recessive mode, with sporadic cases arising de novo.Despite recent important discoveries in the molecular pathogenesis of CE, the molecular causes remain to be identified in about 70% of the patients.With the objective of collecting all the published and unpublished cases of CE the COST action MPN&MPNr-Euronet developed a comprehensive internet-based database focusing on the registration of clinical history, hematological, biochemical and molecular data (http://www.erythrocytosis.org/). In addition, unreported mutations are also curated in the corresponding Leiden Open Variation Database (LOVD).

Frequent EPAS1/HIF2α exons 9 and 12 mutations in non-familial pheochromocytoma

“…Rarely, patients with polycythemia, a disease state characterized by an elevated concentration of red blood cells, have mutations in VHL, EGLN1 or in EPAS1, the gene encoding HIF2a (Bento et al 2014). Recently, somatic gain-offunction mutations in EPAS1 have been reported for the first time, to our knowledge, in paragangliomas associated with polycythemia (Zhuang et al 2012), providing an additional link between polycythemia and neuroendocrine tumors and also supporting the hypothesis of pseudo-hypoxia as an important process in their development.…”

Gene panel sequencing improves the diagnostic work-up of patients with idiopathic erythrocytosis and identifies new mutations

“…41,42 Congenital erythrocytosis also occurs in patients who are compound heterozygotes, [43][44][45] but heterozygous carriers are usually unaffected. Nevertheless, VHL p.R200W heterozygous mutations feature significantly more frequently in erythrocytosis databases 3 than in general populations, 46 suggesting a causal role for this mutation. For one of the four patients here, the variant was newly identified.…”

“…Overall, these results demonstrate the benefits of using a gene panel rather than existing methods in which focused genetic screening is performed depending on biochemical measurements: the gene panel improves diagnostic accuracy and provides the opportunity for discovery of novel variants. erythrocytosis, 2,3 while JAK2 mutations are predominantly associated with primary acquired erythrocytosis i.e. polycythemia vera.…”

“…3,9 About two thirds of these patients have inappropriately normal or elevated erythropoietin levels suggesting a defect in oxygen-sensing or oxygen delivery pathways. Most patients have early-onset disease and/or often a family history, suggesting a high probability of genetic etiology.…”

Investigation and Management of Erythrocytosis

“…A mouse model of the mutation provided further evidence that this mutation as a cause of erythrocytosis [10]. A number of further mutations in PHD2 have now been documented in individuals with congenital erythrocytosis [11]. One of these has been identified in a nearby codon in PHD2, resulting in an A1121G change and a His374Arg amino acid substitution.…”