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Test ID: VHLE VHL Gene, Erythrocytosis Mutation Analysis

Useful For

Diagnosis of suspected JAK2-negative VHL-related erythrocytosis associated with lifelong sustained increased RBC mass, elevated RBC count, hemoglobin, or hematocrit

Method Name

Polymerase Chain Reaction (PCR) Followed by DNA Sequence Analysis

Reporting Name

VHL Gene Erythrocytosis Mutations

Specimen Type

Varies


Specimen Required


Only orderable as part of a profile. For more information see HEMP / Hereditary Erythrocytosis Mutations.

 

This test is only available as a reflex from the HEMP / Hereditary Erythrocytosis Mutations. VHLE is not a single orderable test.


Specimen Minimum Volume

Blood: 1 mL

Specimen Stability Information

Specimen Type Temperature Time
Varies Ambient (preferred)
  Frozen 
  Refrigerated 

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, or secondary, in response to increased serum erythropoietin 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 paraganglioma formation. It is caused by mutations in several genes, including VHL, 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, hemoglobin-stabilization proteins (2,3 bisphosphoglycerate mutase: BPGM), the erythropoietin receptor (EPOR), and oxygen-sensing pathway enzymes (hypoxia-inducible factor: HIF/EPAS1, prolyl hydroxylase domain: PHD2/EGLN1, and 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 typically have normal p50 results. The true prevalence of hereditary erythrocytosis causing mutations is unknown.

 

Genes Associated with Hereditary Erythrocytosis

Gene

Inheritance

Serum Epo

p50

JAK2 V617F

Acquired

Decreased

Normal

JAK2 exon 12

Acquired

Decreased

Normal

EPOR

Dominant

Decreased to normal level

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 proteasomal degradation, which requires prolyl hydroxylation of HIF proline residues. Mutations resulting in altered VHL proteins can lead to familial erythrocytosis, type 2 (ECYT2; OMIM 263400). ECYT2 is a clinically heterogeneous disorder characterized by congenital erythrocytosis with or without high serum EPO levels, venous and arterial thrombosis, and pulmonary hypertension that can manifest as early as infancy but more typically into adulthood. An increased risk for tumors associated with von Hippel-Lindau syndrome, which is also caused by mutations in the VHL gene, has not been observed.

Reference Values

Only orderable as part of a profile. For more information see HEMP / Hereditary Erythrocytosis Mutations.

 

An interpretive report will be provided.

Interpretation

Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics recommendations as a guideline.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

 

Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.

Clinical Reference

1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405-423

2. Online Mendelian inheritance in Man-OMIM. Available from URL: http://www.omim.org/entry/263400

3. Bento C, Percy M, Gardie B, et al: Genetic basis of congenital erythrocytosis: mutation update and online databases. Hum Mutat 2014;35(1):15-26

4. Pastore Y, Jedlickova K, Guan Y, et al: Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia. Am J Hum Genet 2003;73(2):412-419

5. Merchant SH, Oliveira JL, Hoyer JD, et al: Molecular Diagnosis. In Hematopathology. Second edition, Series editor John Goldblum. Edited by ED His. Churchill Livingstone. Hematopathology: A Volume in Foundations in Diagnostic Pathology Series. 2012

Day(s) and Time(s) Performed

Performed weekly, Varies

Analytic Time

14 days

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 U.S. Food and Drug Administration.

CPT Code Information

81404-VHL (von Hippel-Lindau tumor suppressor) (eg, von Hippel-Lindau familial cancer syndrome), full gene sequence

LOINC Code Information

Test ID Test Order Name Order LOINC Value
VHLE VHL Gene Erythrocytosis Mutations 82528-1

 

Result ID Test Result Name Result LOINC Value
37840 Result Summary 50397-9
37841 Result 82528-1
37842 Interpretation 69047-9
37886 Known Mut Reason for Referral 42349-1
37843 Additional Information 48767-8
37844 Specimen 31208-2
37845 Source 31208-2
37846 Released By No LOINC Needed
Mayo Medical Laboratories | Genetics and Pharmacogenomics Catalog Additional Information:

mml-inherited-molecular