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Pyruvate Kinase Deficiency with Hemolytic Anemia via the PKLR Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
PKLR 81405 81405,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8313PKLR81405 81405,81479 $990 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.


Genetic Counselors


  • Luke Drury, PhD

Clinical Features and Genetics

Clinical Features

Pyruvate kinase deficiency (PKD) is a relatively common enzymatic defect in red blood cells affecting an estimated one in 20,000 people and is the leading cause of hereditary nonspherocytic hemolytic anemia (Beutler and Gelbart 2000). Patients affected with this chronic hemolytic anemia exhibit pale skin, jaundice, fatigue, dyspnea, and tachycardia. Splenomegaly, excess iron in the blood, and gall stones are also common symptoms associated with PKD. Disease severity ranges from life threatening in infancy requiring regular blood transfusions to asymptomatic. Symptoms may be exacerbated by underlying infections. Other disorders have been associated with inherited hemolytic anemia including hereditary spherocytosis (via the ANK1, SPTB, SPTA1, EPB42, and SLC4A1 genes) and glucose-6-phosphate deficiency (via the G6PD gene) (Frank 2005; An and Mohandas 2008). PKD may be masked by reticulocytosis. Symptoms are similar to other forms of congenital hemolytic anemia. Genetic testing is helpful for differential diagnosis of distinct congenital hemolytic anemias and for distinguishing between inherited and acquired forms of the disease (Vercellati et al. 2013). Treatment for PKD includes blood transfusions, folic acid supplementation and in severe cases bone marrow transplantation or splenectomy (Zanella et al. 2005).


PKD is inherited in an autosomal recessive manner through mutation in the PKLR gene. The PKLR gene uses alternative promoters to encode the shorter liver specific and longer red blood cell specific isoforms. Mutations identified are found throughout the coding region with missense (65%), splicing (11%), and nonsense (5%) being most prevalent (Zanella et al. 2005). Frameshift and small indel mutations make up 12% of causative variants. Gross deletions have been reported in a minority of cases with the Gypsy deletion, loss of exon 11, and PK ‘Viet’, loss of exons 4-10, being most common (Baronciani and Beutler 1995; Fermo et al 2005). Two substitution mutations have been found within the promoter region leading to disruption of GATA1 transcription factor binding (c.-72C>G) and alteration of the PKLR regulatory element (c.-83G>C ) (Manco et al. 2000; van Wijk et al. 2003). Founder missense mutations play an important role with the c.1529G>A resulting in p.Arg510Gln variant being found in ~40% of North American and Central European patients (Baronciani and Beutler 1995; Lenzer et al. 1997). The c.1456C>T mutation resulting in p.Arg486Trp is found in ~30% of Southern Europeans. The PKRL gene encodes pyruvate kinase which catalyzes the transphosphorylation of phosphoenolpyruvate to ADP yielding ATP and pyruvate. This metabolic reaction is the last step in glycolysis and is essential for providing ATP energy to red blood cells, which rely heavily on glycolysis for energy due to their lack of mitochondria (Zanella et al. 2005).

Clinical Sensitivity - Sequencing with CNV PGxome

In patients with biochemical evidence indicating pyruvate kinase deficiency, 58 of 60 and 53 of 58 had mutations within the PKLR gene (Baronciani and Beutler 1995; Lenzner et al. 1997). Analytical sensitivity for identifying PKLR mutations by this sequencing method is >95% as large deletions have been reported only in a few cases.

Testing Strategy

This test provides full coverage of all coding exons of the PKLR gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Candidates for this test are patients showing features consistent with PKD (anemia, increased LDH, decreased haptoglobin and jaundice. Ideal candidates have biochemical results indicating impaired pyruvate kinase enzymatic activity and a family history for the disorder (Aster et al. 2013). Unlike congenital spherocytic hemolytic anemias, red blood cells are non-spheroid and osmotic fragility is normal. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in PKLR.


Official Gene Symbol OMIM ID
PKLR 609712
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Pyruvate Kinase Deficiency AR 266200


  • An X, Mohandas N. 2008. Disorders of red cell membrane. Br. J. Haematol. 141: 367–375. PubMed ID: 18341630
  • Aster, JC, Pozdnyakova, O, Kutok, JL. Hematopathology. Philadelphia: Elsevier Saunders, 2013.
  • Baronciani L, Beutler E. 1995. Molecular study of pyruvate kinase deficient patients with hereditary nonspherocytic hemolytic anemia. J. Clin. Invest. 95: 1702–1709. PubMed ID: 7706479
  • Beutler E, Gelbart T. 2000. Estimating the prevalence of pyruvate kinase deficiency from the gene frequency in the general white population. Blood 95: 3585–3588. PubMed ID: 10828047
  • Fermo E, Bianchi P, Chiarelli LR, Cotton F, Vercellati C, Writzl K, Baker K, Hann I, Rodwell R, Valentini G, Zanella A. 2005. Red cell pyruvate kinase deficiency: 17 new mutations of the PK-LR gene. Br. J. Haematol. 129: 839–846. PubMed ID: 15953013
  • Frank JE. 2005. Diagnosis and management of G6PD deficiency. Am Fam Physician 72: 1277–1282. PubMed ID: 16225031
  • Lenzner C, Nürnberg P, Jacobasch G, Gerth C, Thiele BJ. 1997. Molecular analysis of 29 pyruvate kinase-deficient patients from central Europe with hereditary hemolytic anemia. Blood 89: 1793–1799. PubMed ID: 9057665
  • Manco L, Ribeiro ML, Máximo V, Almeida H, Costa A, Freitas O, Barbot J, Abade A, Tamagnini G. 2000. A new PKLR gene mutation in the R-type promoter region affects the gene transcription causing pyruvate kinase deficiency. Br. J. Haematol. 110: 993–997. PubMed ID: 11054094
  • Vercellati C, Marcello AP, Fermo E, Barcellini W, Zanella A, Bianchi P. 2013. A case of hereditary spherocytosis misdiagnosed as pyruvate kinase deficient hemolytic anemia. Clin. Lab. 59: 421–424. PubMed ID: 23724634
  • Wijk R van, Solinge WW van, Nerlov C, Beutler E, Gelbart T, Rijksen G, Nielsen FC. 2003. Disruption of a novel regulatory element in the erythroid-specific promoter of the human PKLR gene causes severe pyruvate kinase deficiency. Blood 101: 1596–1602. PubMed ID: 12393511
  • Zanella A, Fermo E, Bianchi P, Valentini G. 2005. Red cell pyruvate kinase deficiency: molecular and clinical aspects. Br. J. Haematol. 130: 11–25. PubMed ID: 15982340


Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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