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Test ID: PHD2    
Prolyl Hydroxylase Domain-2 (PHD2/EGLN1) Gene Sequencing

Available on the App Store

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 / 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.

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 / 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 / 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 / Hereditary Erythrocytosis Mutations. 

Clinical Reference Provides recommendations for further in-depth reading of a clinical nature