Primary Familial and Congenital Polycythemia (PFCP) via the EPOR Gene

Primary familial and congenital polycythemia (PFCP), also known as familial erythrocytosis, is a disorder characterized by heightened red blood cell levels. Clinical symptoms range and may include headaches, dizziness, nosebleeds, and shortness of breath. PFCP may be asymptomatic, but it has been associated with predisposition to cardiovascular problems and abnormal clotting (Gordeuk et al. 2005; Huang et al. 2010). There are four forms of familial polycythemia defined by which gene is mutated: type 1-EPOR, type-2 VHL, type 3-EGLN1, and type 4-EPAS1 (Hussein et al. 2012). Erythrocytosis may also be acquired due to long term high altitude exposure, cardiac disorders characterized by hypoxia, chronic lung disease, and sleep apnea. PFCP symptoms mirror a second disorder, Polycythemia Vera, which is due to mutations in the JAK2 gene. Unlike PFCP, patients with Polycythemia Vera are at heightened risk for developing myeloid proliferative cancers (Etheridge et al. 2014). Phlebotomy has been shown to relieve clinical symptoms. Genetic testing is helpful in differential diagnosis of acquired and inherited forms as well as distinct inherited subtypes of erythrocytosis (Gordeuk et al. 2005).

PFCP is inherited in an autosomal dominant manner through mutations in the EPOR gene. Three other forms of familial polycythemia are inherited in an autosomal recessive manner through mutations in the VHL, EGLN1, and EPAS1 genes. Approximately twenty-five mutations have been identified in the EPOR gene to date with the majority being truncating or frameshift mutations within the c-terminus of the protein (Huang et al. 2010; Kralovics et al. 1997; Forget et al. 2000; Al-Sheikh et al. 2008). Two reports have identified missense mutations in the EPOR gene in individuals diagnosed with PFCP, but the functional significance of these mutations is still unclear (Le Couedic et al. 1996; Huang et. al. 2010). No gross deletions or duplications have been reported. The EPOR gene encodes the erythropoietin receptor and binds erythropoietin, an essential cytokine to promote terminal differentiation of erythrocytes. Truncating mutations in the c-terminus of the EPOR gene lead to loss of the intracellular cytoplasmic tail of the receptor. Upon ligand binding, truncated receptors have prolonged signaling due to loss of the negative regulatory domain resulting in hypersensitivity to erythropoietin (Huang et al. 2010; Gordeuk et al. 2005).

Analytical sensitivity should be high because all mutations reported are detectable by this method. Clinical sensitivity is estimated to be <50% with one report indicating only 12% (5 of 43) patients having a mutation within the EPOR gene in patients diagnosed with PFCP (Kralovics and Prchal 2001).

No gross deletions or duplications have been reported in EPOR (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the EPOR gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).