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Test ID: HEMP Hereditary Erythrocytosis Mutations, Whole Blood

Reporting Name

Hereditary Erythrocytosis Mut, B

Useful For

Definitive evaluation of an individual with JAK2-negative erythrocytosis associated with lifelong sustained increased red blood cell (RBC) mass, elevated RBC count, hemoglobin, or hematocrit

 

This test is not intended for prenatal diagnosis.

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

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 variant should not be present. Additionally, p50 testing should be performed and a normal result confirmed before ordering this test.

 

Additional testing for BPGM full gene sequencing and VHL gene erythrocytosis variant analysis will always be performed at an additional charge.

 

See Erythrocytosis Evaluation Testing Algorithm in Special Instructions.

Specimen Type

Whole blood


Ordering Guidance


This is a third-order test for specific variants. For a complete evaluation including p50 testing, hemoglobin electrophoresis testing, and hereditary erythrocytosis variant analysis in an algorithmic fashion, order REVE1 / Erythrocytosis Evaluation, Whole Blood.

 

This test does not provide a serum erythropoietin (EPO) level. If EPO testing is desired, see EPO / Erythropoietin, Serum.



Specimen Required


Container/Tube: Lavender top (EDTA)

Specimen Volume: 3 mL

Collection Instructions: Send specimen in original tube.


Specimen Minimum Volume

0.5 mL

Specimen Stability Information

Specimen Type Temperature Time Special Container
Whole blood Refrigerated (preferred) 30 days
  Ambient  14 days

Reference Values

An interpretive report will be provided.

Day(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 red blood cell [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 variations 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 variants 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 variants is unknown. The hemoglobin genes, HBA1/HBA2 and HBB are not assayed in this profile.

 

Genes Associated with Hereditary Erythrocytosis

Gene

Inheritance

Serum EPO

p50

JAK2 V617F

Acquired

Decreased

Normal

JAK2 exon 12

Acquired

Decreased

Normal

EPOR

Dominant

Decreased

Normal

PHD2/EGLN1

Dominant

Normal level

Normal

BPGM

Recessive

Normal level

Decreased

Beta globin

Dominant

Normal level to increased

Decreased

Alpha globin

Dominant

Normal level to increased

Decreased

HIF2A/EPAS1

Dominant

Normal level to increased

Normal

VHL

Recessive

Normal to increased

Normal

 

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 (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 (EGLN1) gene. Variations resulting in altered HIF-alpha, PHD2, and VHL proteins can lead to clinical erythrocytosis. A small subset of variants, in PHD2/EGLN1 and HIF2A/EPAS1, has also been detected in erythrocytic patients presenting with paragangliomas or pheochromocytomas.

 

Truncating variants 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 variants have been localized to exon 8 and are heterozygous truncating variants. EPOR variants are associated with decreased EPO levels and normal p50 values (see Table).

Interpretation

An interpretive report will be provided and will include specimen information, assay information, and whether the specimen was positive for any variations in the gene. If positive, the variant 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: His ED, ed. Hematopathology. 2nd ed. Elsevier Saunders; 2012:22-723

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

11. Tarade D, Robinson CM, Lee JE, Ohh M: HIF-2alpha-pVHL complex reveals broad genotype-phenotype correlations in HIF-2aalpha-driven disease. Nat Commun. 2018;9(1):3359

12. Oliveira JL: Algorithmic evaluation of hereditary erythrocytosis: Pathways and caveats. Int J Lab Hematol. 2019 May;41 Suppl 1:89-94

Report Available

10 to 25 days

Method Name

Polymerase Chain Reaction (PCR) Amplification/Sanger Sequence Analysis

Forms

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.

Additional Tests

Test ID Reporting Name Available Separately Always Performed
BPGMM BPGM Full Gene Sequencing Yes Yes
VHLE VHL Gene Erythrocytosis Mutations No, (Order VHLZ) Yes

Test Classification

This test was developed, and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the US Food and Drug Administration.
Mayo Clinic Laboratories | Genetics and Pharmacogenomics Catalog Additional Information:

mml-inherited-molecular