Hereditary Thrombocythemia via the THPO Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1647 THPO$650.00 81479 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity

Mutations in the JAK2 and MPL genes account for ~50% and 4% of patient with HT respectively (Beer and Green 2009). Clinical sensitivity for HT cases due to THPO mutations is unknown at this time (Hussein et al. 2013). Analytical sensitivity should be high because all mutations reported are detectable by this method.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 THPO$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Features

Hereditary Thrombocythemia (HT) is a myeloproliferative condition characterized by chronic high platelet numbers. Most common symptoms include headache, lightheadedness, vision changes, numbness and burning pain in the hands and feet. Less common, but more severe, symptoms include abnormal clotting (thrombosis), and leukemic transformation. Alternatively, patients may also exhibit bleeding episodes leading to nosebleeds, bleeding gums, and/or gastrointestinal bleeds (Brière 2007; Teofili and Larocca 2011). This is thought to occur due to acquired von Willebrand disease (Michiels 1999). Diagnosis of HT typically involves exclusion of secondary thrombocythemia causes including chronic infection, iron deficiency, myeloproliferative malignancies, and acute blood loss. Germline mutation in the MPL gene or somatic mutation in the JAK2 gene have also been reported to cause thrombocythemia (Beer and Green 2009). Importantly, patients with JAK2 mutations are at heightened risks to develop myeloproliferative cancers whereas THPO and MPL mutations are typically non-neoplastic (Nielsen et al. 2011). Therefore, genetic testing can aid greatly in distinguishing HT from secondary thrombocythemia causes and predicting neoplastic risk through confirmation of the causative gene.


There are three forms of HT. Type I is inherited in an autosomal dominant manner through mutation in the THPO gene. Type II is inherited in both autosomal dominant and recessive manners through mutation in the MPL gene. Type III is inherited or acquired somatically in an autosomal dominant manner with reduced penetrance through mutation in the JAK2 gene (Hussein et al 2013). Causative mutations within the THPO gene are primarily splice alterations and upstream substitutions impairing transcription (Hussein et al. 2013; Zhang et al. 2011; Wiestner et al. 1998). One missense mutation, p.Arg38Cys, leading to loss of protein function has also been reported (Dasouki et al. 2013). The THPO gene encodes the protein thrombopoietin with stimulates production of megakaryocytes and their differentiation into platelets.

Testing Strategy

Our DNA sequencing test involves bidirectional sequencing of the entire THPO gene plus ~10 bp of flanking non-coding DNA on either side of each exon. We will also sequence any single exon (Test #100) in family members of patients with a known mutation or to confirm research results.

Indications for Test

Patients with chronically elevated platelet counts (>450 x 109/l) and proliferation in only the megakaryocyte lineage are primary indications for HT. Please refer to Tefferi et al. 2007 for a more detailed diagnostic guide for HT.


Official Gene Symbol OMIM ID
THPO 600044
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Essential Thrombocythemia 187950


Genetic Counselors
  • Beer PA, Green AR. 2009. Pathogenesis and management of essential thrombocythemia. Hematology Am Soc Hematol Educ Program 621–628. PubMed ID: 20008247
  • Brière JB. 2007. Essential thrombocythemia. Orphanet J Rare Dis 2: 1–17. PubMed ID: 17210076
  • Dasouki MJ, Rafi SK, Olm-Shipman AJ, Wilson NR, Abhyankar S, Ganter B, Furness LM, Fang J, Calado RT, Saadi I. 2013. Exome sequencing reveals a thrombopoietin ligand mutation in a Micronesian family with autosomal recessive aplastic anemia. Blood 122: 3440–3449. PubMed ID: 24085763
  • Hussein K, Granot G, Shpilberg O, Kreipe H. 2013. Clinical utility gene card for: familial polycythaemia vera. European Journal of Human Genetics 21: PubMed ID: 23032109
  • Hussein K, Percy M, McMullin MF, Schwarz J, Schnittger S, Porret N, Martinez-Aviles LM, Paricio BB, Giraudier S, Skoda R, Lippert E, Hermouet S, et al. 2014. Clinical utility gene card for: Hereditary thrombocythemia. European Journal of Human Genetics 22: PubMed ID: 23736217
  • Michiels JJ. 1999. Acquired von Willebrand disease due to increasing platelet count can readily explain the paradox of thrombosis and bleeding in thrombocythemia. Clin. Appl. Thromb. Hemost. 5: 147–151. PubMed ID: 10725999
  • Nielsen C, Birgens HS, Nordestgaard BG, Kjaer L, Bojesen SE. 2011. The JAK2 V617F somatic mutation, mortality and cancer risk in the general population. Haematologica 96: 450–453. PubMed ID: 21160067
  • Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA, Barosi G, Verstovsek S, Birgegard G, Mesa R, Reilly JT, Gisslinger H, et al. 2007. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood 110: 1092–1097. PubMed ID: 17488875
  • Teofili L, Larocca LM. 2011. Advances in understanding the pathogenesis of familial thrombocythaemia: Review. British Journal of Haematology 152: 701–712. PubMed ID: 21303356
  • Wiestner A, Schlemper RJ, Maas AP van der, Skoda RC. 1998. An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia. Nat. Genet. 18: 49–52. PubMed ID: 9425899
  • Zhang B, Ng D, Jones C, Oh ST, Nolan GP, Salehi S, Wong W, Zehnder JL, Gotlib J. 2011. A novel splice donor mutation in the thrombopoietin gene leads to exon 2 skipping in a Filipino family with hereditary thrombocythemia. Blood 118: 6988–6990. PubMed ID: 22194398
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 10 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

Ordering Options

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.
  • 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.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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