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Test Code BPGMM 2,3-Bisphosphoglycerate Mutase, Full Gene Sequencing Analysis, Varies

Useful For

Diagnosing 2,3-bisphosphoglycerate mutase deficiency in individuals with lifelong, unexplained erythrocytosis

 

Identifying genetic variant carriers in family members of an affected individual for the purposes of preconception genetic counseling

 

This test is not intended for prenatal diagnosis.

Genetics Test Information

The BPGM gene encodes the enzyme 2,3-bisphosphoglycerate mutase (BPGM) that catalyzes the conversion of 1,3-bisphosphoglycerate to 2,3-bisphosphoglycerate (2,3-BPG), also known as 2,3-diphosphoglycerate (2,3-DPG), through the Luebering-Rapoport pathway. 2,3-BPG is a small molecule generated from glycolysis and is present in large amounts in red blood cells. It functions to stabilize the hemoglobin molecule and facilitates oxygen unloading at tissue sites. Therefore, 2,3-BPG concentrations affect the oxygen affinity of hemoglobin. Variations in this gene that result in a deficiency of 2,3-BPG can cause hereditary erythrocytosis.

 

This test can detect variants in BPGM that are associated with unexplained lifelong erythrocytosis due to bisphosphoglycerate mutase deficiency.

Testing Algorithm

This evaluation is recommended for patients presenting with lifelong elevation in hemoglobin or hematocrit, usually with a positive family history of similar symptoms. Reported cases of 2,3- bisphosphoglycerate deficiency have been associated with decreased p50 values (left-shifted oxygen-dissociation curve). Due to the rarity of this disorder, other more common causes of erythrocytosis should be excluded prior to ordering; for more information see Erythrocytosis Evaluation Testing Algorithm .

 

Polycythemia vera and chronic myeloproliferative neoplasm should be excluded prior to testing as they are more common causes of elevated hemoglobin values. A JAK2 V617F or JAK2 exon 12 variant should not be present. Patient serum erythropoietin levels are typically normal or elevated.

Method Name

Polymerase Chain Reaction (PCR)/Sanger Sequencing

Reporting Name

BPGM Full Gene Sequencing

Specimen Type

Varies


Ordering Guidance


This test detects variants identifiable by Sanger sequencing in the BPGM gene only. For a reflexive evaluation including hemoglobin electrophoresis and variant analysis of genes associated with hereditary erythrocytosis, order REVE2 / Erythrocytosis Evaluation, Blood.

 

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



Necessary Information


Erythrocytosis Patient Information (T694) is strongly recommended, but not required, to be filled out and sent with the specimen. This information aids in providing a more thorough interpretation of test results. Ordering providers are strongly encouraged to complete the form and send it with the specimen.



Specimen Required


Submit only 1 of the following specimens:

 

Patient Preparation: Bone marrow transplants preclude accurate germline and genetic variant analysis. Inform the laboratory if this patient has undergone bone marrow transplantation. On rare occasions transfusion of blood products can preclude accurate genetic variant analysis, and results should be interpreted with caution if performed after recent transfusion (within 4 months).

 

Specimen Type: Whole blood

Container/Tube:

Preferred: Lavender top (EDTA)

Acceptable: Yellow top (ACD), green top (sodium heparin)

Specimen Volume: 4 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send whole blood specimen in the original tube. Do not aliquot

Specimen Stability Information: Ambient 14 days (preferred)/Refrigerate 30 days

 

Specimen Type: Extracted DNA from whole blood

Container/Tube: 1.5 to 2 mL tube

Specimen Volume: Entire specimen

Collection Instructions:

1. Label specimen as extracted DNA and source of specimen

2. Provide volume and concentration of the DNA

Specimen Stability Information: Frozen (preferred)/Refrigerate/Ambient


Specimen Minimum Volume

Blood: 1 mL; Extracted DNA: 50 mcL at 50 ng/mcL concentration

Specimen Stability Information

Specimen Type Temperature Time Special Container
Varies Varies

Reject Due To

Gross hemolysis Reject
Bone marrow
Paraffin-embedded tissue
Frozen tissue
Paraffin-embedded bone marrow aspirate clot
Methanol-acetic acid (MAA)-fixed pellets
Moderately to severely clotted		 Reject

Clinical Information

Erythrocytosis (ie, increased red blood cell mass and elevated hemoglobin and hematocrit) may be primary, due to an intrinsic defect of bone marrow stem cells as in 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, cyanotic heart disease, high-altitude living, kidney 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 mechanism may be suspected.

 

Unlike PV, hereditary erythrocytosis is not associated with the risk of clonal evolution and most commonly presents as isolated erythrocytosis that has been present since childhood. Hereditary erythrocytosis may be caused by alterations in one of several genes and inherited in either an autosomal dominant or autosomal recessive manner.

 

Genetic variants causing hereditary erythrocytosis have been found in genes coding for alpha and beta hemoglobins, hemoglobin stabilization proteins (eg, 2,3-bisphosphoglycerate mutase: BPGM), the erythropoietin receptor (EPOR), and oxygen-sensing pathway enzymes (hypoxia-inducible factor: HIF, prolyl hydroxylase domain: PHD, and von Hippel Lindau: VHL), see Table. The true prevalence of variants causing hereditary erythrocytosis is unknown; however, very few cases of 2,3-BPG deficiency-associated hereditary erythrocytosis have been identified, and this disorder is thought to be rare.

 

Table. Erythrocytosis Testing

Gene

Inheritance

Serum EPO

JAK2 V617F

Acquired

Decreased

JAK2 exon 12

Acquired

Decreased

EPOR

Dominant

Decreased

PHD2/EGLN1

Dominant

Normal

BPGM

Recessive

Normal

Beta globin

Dominant

Normal to increased

Alpha globin

Dominant

Normal to increased

HIF2A/EPAS1

Dominant

Normal to increased

VHL

Recessive

Normal to increased

Reference Values

An interpretive report will be provided.

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 alteration will be correlated with clinical significance, if known.

Cautions

This test does not detect large deletions and duplications in BPGM.

 

Polycythemia vera and acquired causes of erythrocytosis should be excluded before ordering this test.

 

Certain genetic alterations have no clinical manifestations and, in essence, are clinically benign. Correlation with all relevant clinical information is necessary to provide appropriate patient care.

Method Description

DNA is extracted from whole peripheral blood and amplified in 4 separate polymerase chain reactions (PCR) to cover BPGM exons 1 through 4. PCR products are then sequenced by the Sanger sequencing method and analyzed with sequencing software. Patient sequence results are compared with the genomic reference sequences and the single-nucleotide variants known to occur in the genes. If a variant is detected, the messenger RNA reference sequence will be used to determine the amino acid number and resulting amino acid change if there is one.(Lemarchandel V, Joulin V: Compound heterozygosity in a complete erythrocyte bisphosphoglycerate mutase deficiency. Blood. 1992 Nov;80[10]:2643-2649; McMullin MF: Congenital erythrocytosis. IJLH 2016;38[Suppl. 1]:59-65)

Day(s) Performed

Monday through Friday

Report Available

10 to 25 days

Performing Laboratory

Mayo Clinic Laboratories in Rochester

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.

CPT Code Information

81479

LOINC Code Information

Test ID Test Order Name Order LOINC Value
BPGMM BPGM Full Gene Sequencing 94190-6

 

Result ID Test Result Name Result LOINC Value
37111 BPGM Gene Sequencing Result No LOINC Needed
37112 BPGM Interpretation 69047-9