Test ID: PHD2
Prolyl Hydroxylase Domain-2 (PHD2/EGLN1) Gene Sequencing
NY State Approved 
Indicates the status of NY State approval and if the test is orderable for NY State clients.
Useful For Suggests clinical disorders or settings where the test may be helpful
Only orderable as part of a profile. For further information see HEMP/61337 Hereditary Erythrocytosis Mutations.
Genetics Test Information Provides information that may help with selection of the correct test or proper submission of the test request
This test is a third-order test and should be ordered when the patient meets the following criteria: diagnosis of erythrocytosis, serum erythropoietin levels are normal, and p50 values are normal.
Testing Algorithm Delineates situation(s) when tests are added to the initial order. This includes reflex and additional tests.
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. Serum Epo levels are typically normal (inappropriately so for the level of hemoglobin). For a complete evaluation including p50 testing, hemoglobin electrophoresis testing, and hereditary erythrocytosis mutation analysis in an algorithmic fashion, order the erythrocytosis evaluation panel (REVP/84160).
Method Name A short description of the method used to perform the test
Polymerase Chain Reaction (PCR) Amplification/Sanger Sequence Analysis
Reporting Name A shorter/abbreviated version of the Published Name for a test; an abbreviated test name
Aliases Lists additional common names for a test, as an aid in searching
Specimen Type Describes the specimen type needed for testing
Specimen Required Defines the optimal specimen. This field describes the type of specimen required to perform the test and the preferred volume to complete testing. The volume allows automated processing, fastest throughput and, when indicated, repeat or reflex testing.
Only orderable as part of a profile. For further information see HEMP/61337 Hereditary Erythrocytosis Mutations.
Specimen Minimum Volume Defines the amount of specimen required to perform an assay once, including instrument and container dead space. Submitting the minimum specimen volume makes it impossible to repeat the test or perform confirmatory or perform reflex testing. In some situations, a minimum specimen volume may result in a QNS (quantity not sufficient) result, requiring a second specimen to be collected.
Specimen Stability Information Provides a description of the temperatures required to transport a specimen to the laboratory. Alternate acceptable temperature(s) are also included.
| Specimen Type | Temperature | Time |
|---|---|---|
| Whole blood | Refrigerated | 30 days |
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Erythrocytosis (increased RBC mass or polycythemia) may be primary, due to an intrinsic defect of bone marrow stem cells (polycythemia vera: PV), or secondary, in response to increased 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 extrinsic causes of erythrocytosis are excluded, a heritable cause intrinsic to the RBC or erythrocyte regulatory mechanisms may be suspected.
Mutations in genes coding for hemoglobin (high-oxygen-affinity hemoglobin variants), hemoglobin-stabilization proteins (2,3 bisphosphoglycerate deficiency), the erythropoietin receptor and oxygen-sensing pathway enzymes (hypoxia-inducible factor, prolyl hydroxylase domain, and von Hippel Lindau) can result in erythrocytosis (see Table).
Erythrocytosis Testing | |||
| Gene | Inheritance | Serum EPO | p50 |
| JAK2V617F | Acquired | Decreased | Normal |
| JAK2 exon 12 | Acquired | Decreased | Normal |
| EPOR | Dominant | Decreased to Normal | Normal |
| PHD2 | Dominant | Normal | Normal |
| BPGM | Dominant | Normal | Decreased |
| Beta Globin | Dominant | Increased to Normal | Decreased |
| Alpha Globin | Dominant | Increased to Normal | Decreased |
| HIF2A | Dominant | Increased to Normal | Normal |
| VHL | Recessive | Increased | Normal |
The oxygen sensing pathway functions through an enzyme, hypoxia-inducible factor (HIF) that 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. HIF-alpha is regulated by von Hippel-Lindau (vHL) protein-mediated ubiquitination and proteosomal degradation, which requires prolyl hydroxylation of the serine and histidine residues. Enzymes important in the hydroxylation of HIF are the prolyl hydroxylase domain proteins, which have 3 isoforms-PHD1, PHD2, and PHD3. The most significant isoform associated with erythrocytosis is PHD2. PHD enzymes are oxygen dependent and have an iron-containing active site. Ascorbic acid enhances, but is not essential for, the activity of PHD. Therefore, activity can be modulated by low iron and ascorbic acid levels as well as by low oxygen. Clinically significant PHD2 (official designation EGLN1 [egl nine homolog 1]) mutations are heterozygous and have been found in exons 1 through 4. These mutations result in amino acid substitutions and are associated with inappropriately normal EPO levels.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
Only orderable as part of a profile. For further information see HEMP/61337 Hereditary Erythrocytosis Mutations.
Interpretation Provides information to assist in interpretation of the test results
Only orderable as part of a profile. For further information see HEMP/61337 Hereditary Erythrocytosis Mutations.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Only orderable as part of a profile. For further information see HEMP/61337 Hereditary Erythrocytosis Mutations.
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
Method Description Describes how the test is performed and provides a method-specific reference
Only orderable as part of a profile. For further information see HEMP/61337 Hereditary Erythrocytosis Mutations.
Performing Laboratory Location The location of the laboratory that performs the test
Test Classification Provides information regarding the medical device classification for laboratory test kits and reagents. Tests may be classified as cleared or approved by the US Food and Drug Administration (FDA) and used per manufacturer's instructions, or as products that do not undergo full FDA review and approval, and are then labeled as an Analyte Specific Reagent (ASR), Investigation Use Only (IUO) product, or a Research Use Only (RUO) product.
CPT Code Information Provides guidance in determining the appropriate Current Procedural Terminology (CPT) code(s) information for each test or profile. The listed CPT codes reflect Mayo Medical Laboratories interpretation of CPT coding requirements. It is the responsibility of each laboratory to determine correct CPT codes to use for billing.
81479-Unlisted molecular pathology procedure
LOINC® Code Information Provides guidance in determining the Logical Observation Identifiers Names and Codes (LOINC) values for the result codes returned for this test or profile.
| Result ID | Reporting Name | LOINC Code |
|---|---|---|
| 34646 | PHD2 Gene Sequencing Result | In Process |
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