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Test ID: HEMP Hereditary Erythrocytosis Mutations

Reporting Name

Hereditary Erythrocytosis Mut, B

Useful For

The definitive evaluation of an individual with JAK2-negative erythrocytosis associated with lifelong sustained increased RBC mass, elevated RBC count, hemoglobin, or hematocrit

Profile Information

Test ID Reporting Name Available Separately Always Performed
MINT Molecular Interpretation No Yes
EPOR EPOR Gene, Mutation Analysis, B No Yes
HIF2A HIF2A Gene, Mutation Analysis, B No Yes
PHD2 PHD2 Gene, Mutation Analysis, B No Yes

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
VHLE VHL Gene Erythrocytosis Mutations No No
BPGMM BPGM Full Gene Sequencing Yes No

Testing Algorithm

This evaluation is recommended for patients presenting with lifelong erythrocytosis, usually with a positive family history of similar symptoms. Polycythemia vera should be excluded prior to testing as it is much more common than hereditary erythrocytosis and can be present even in young patients. A JAK2 V617F or JAK2 exon 12 mutation should not be present. Additionally, p50 testing should be performed and a normal result confirmed before ordering this test. For a complete evaluation including p50 testing, hemoglobin electrophoresis testing, and hereditary erythrocytosis mutation analysis in an algorithmic fashion, order REVE / Erythrocytosis Evaluation. Please note that this test (HEMP) is a reflex test for REVE and should not be ordered if REVE is ordered.


See Erythrocytosis Evaluation Testing Algorithm in Special Instructions.

Specimen Type

Whole blood

Advisory Information

This is a third-order test for specific mutations. For a complete evaluation in an algorithmic fashion, order REVE/ Erythrocytosis Evaluation.

Specimen Required

Container/Tube: EDTA (lavender)

Specimen Volume: 3 mL

Collection Instructions: Send specimen in original tube.

Specimen Minimum Volume

0.5 mL

Specimen Stability Information

Specimen Type Temperature Time
Whole blood Refrigerated 30 days

Reference Values

An interpretive report will be provided.

Day(s) and Time(s) Performed

Monday through Friday

CPT Code Information

81479-Unlisted molecular pathology procedure

LOINC Code Information

Test ID Test Order Name Order LOINC Value
HEMP Hereditary Erythrocytosis Mut, B In Process


Result ID Test Result Name Result LOINC Value
34645 EPOR Gene Sequencing Result 82939-0
34646 PHD2 Gene Sequencing Result 82939-0
34647 HIF2A Gene Sequencing Result 82939-0
34648 Molecular Interpretation 69047-9
35000 Reviewed By 18771-6

Clinical Information

Erythrocytosis (ie, increased RBC mass or polycythemia) may be primary, due to an intrinsic defect of bone marrow stem cells (ie, polycythemia vera: PV), or secondary, in response to increased serum erythropoietin (EPO) levels. Secondary erythrocytosis is associated with a number of disorders including chronic lung disease, chronic increase in carbon monoxide (due to smoking), cyanotic heart disease, high-altitude living, renal cysts and tumors, hepatoma, and other EPO-secreting tumors. When these common causes of secondary erythrocytosis are excluded, a heritable cause involving hemoglobin or erythrocyte regulatory mechanisms may be suspected.


Unlike polycythemia vera, hereditary erythrocytosis is not associated with the risk of clonal evolution and should present with isolated erythrocytosis that has been present since birth. A small subset of cases is associated with pheochromocytoma and/or paraganglioma formation. It is caused by mutations in several genes and may be inherited in either an autosomal dominant or autosomal recessive manner. A family history of erythrocytosis would be expected in these cases, although it is possible for new mutations to arise in an individual.


The genes coding for hemoglobin, beta globin and alpha globin (high-oxygen-affinity hemoglobin variants), hemoglobin-stabilization proteins (2,3 bisphosphoglycerate mutase: BPGM), and the erythropoietin receptor, EPOR, and oxygen-sensing pathway enzymes (hypoxia-inducible factor: HIF/EPAS1, prolyl hydroxylase domain: PHD2/EGLN1, and von Hippel Lindau: VHL) can result in hereditary erythrocytosis (see Table). High-oxygen-affinity hemoglobin variants and BPGM abnormalities result in a decreased p50 result, whereas those affecting EPOR, HIF, PHD, and VHL have normal p50 results. The true prevalence of hereditary erythrocytosis-causing mutations is unknown.


Genes Associated with Hereditary Erythrocytosis



Serum EPO


JAK2 V617F




JAK2 exon 12






Decreased to normal level




Normal level




Normal level


Beta Globin


Normal level to increased


Alpha Globin


Normal level to increased




Normal level to increased




Markedly Increased



The oxygen-sensing pathway functions through an enzyme, hypoxia-inducible factor (HIF), which regulates RBC mass. A heterodimer protein comprised of alpha and beta subunits, HIF functions as a marker of depleted oxygen concentration. When present, oxygen becomes a substrate mediating HIF-alpha subunit degradation. In the absence of oxygen, degradation does not take place and the alpha protein component is available to dimerize with a HIF-beta subunit. The heterodimer then induces transcription of many hypoxia response genes including EPO, VEGF, and GLUT1. HIF-alpha is regulated by von Hippel-Lindau (VHL) protein-mediated ubiquitination and proteosomal degradation, which requires prolyl hydroxylation of HIF proline residues. The HIF-alpha subunit is encoded by the HIF2A (official name EPAS1) gene. Enzymes important in the hydroxylation of HIF-alpha are the prolyl hydroxylase domain proteins, of which the most significant isoform is PHD2, which is encoded by the PHD2 (official name EGLN1) gene. Mutations resulting in altered HIF-alpha, PHD2, and VHL proteins can lead to clinical erythrocytosis. A small subset of mutations, in PHD2 and HIF2A, has also been detected in erythrocytic patients presenting with paragangliomas or pheochromocytomas.


Truncating mutations in the EPOR gene coding for the erythropoietin receptor can result in erythrocytosis through loss of the negative regulatory cytoplasmic SHP-1 binding domain leading to EPO hypersensitivity. All currently known mutations have been localized to exon 8, are mainly missense or small deletion and insertions resulting in stop codons, and are heterozygous. EPOR mutations are associated with decreased to normal EPO levels and normal p50 values (see Table).


An interpretive report will be provided and will include specimen information, assay information, and whether the specimen was positive for any mutations in the gene. If positive, the mutation will be correlated with clinical significance, if known.

Clinical Reference

1. Patnaik MM, Tefferi A: The complete evaluation of erythrocytosis: congenital and acquired. Leukemia 2009 May;23(5):834-844

2. McMullin MF: The classification and diagnosis of erythrocytosis. Int J Lab Hematol 2008;30:447-459

3. Percy MJ, Lee FS: Familial erythrocytosis: molecular links to red blood cell control. Haematologica 2008 Jul;93(7):963-967

4. Huang LJ, Shen YM, Bulut GB: Advances in understanding the pathogenesis of primary familial and congenital polycythaemia. Br J Haematol 2010 Mar;148(6):844-852

5. Maran J, Prchal J: Polycythemia and oxygen sensing. Pathologie Biologie 2004;52:280-284

6. Lee F: Genetic causes of erythrocytosis and the oxygen-sensing pathway. Blood Rev 2008;22:321-332

7. Merchant SH, Oliveira JL, Hoyer JD, Viswanatha DS: Erythrocytosis. In Hematopathology. Second edition. Edited by ED His. Philadelphia, Elsevier Saunders, 2012, pp 22-723

8. Zhuang Z, Yang C, Lorenzo F, et al: Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N Engl J Med 2012 Sep 6;367(10):922-930

9. Ladroue C, Carcenac R, Leporrier M, et al: PHD2 mutation and congenital erythrocytosis with paraganglioma. N Engl J Med 2008 Dec 18;359(25):2685-2692

10. Lorenzo FR, Yang C, Ng Tang Fui M, et al: A novel EPAS1/HIF2A germline mutation in congenital polycythemia with paraganglioma. J Mol Med 2013 Apr;91(4):507-512

Analytic Time

10 days

Method Name

Polymerase Chain Reaction (PCR) Amplification/Sanger Sequence Analysis


1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in Special Instructions:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. Erythrocytosis Patient Information (T694) in Special Instructions

3. If not ordering electronically, complete, print, and send a Benign Hematology Test Request Form (T755) with the specimen.

Mayo Clinic Laboratories | Genetics and Pharmacogenomics Catalog Additional Information: