Congenital Amegakaryocytic Thrombocytopenia (CAMT) and Thrombocythemia 2 via the MPL 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
437 MPL$710.00 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

Variants in the MPL gene are the only known cause of Congenital Amegakaryocytic Thrombocytopenia (CAMT). Germline and somatic variants in the JAK2, CALR, and MPL genes are the most frequent causes of myeloproliferative neoplasms (MPNs) (Essential Thrombocythemia - ET; Primary Myelofibrosis - MPF; and polycythemia Vera - PV). The JAK2 variant p.Val617Phe accounts for 97% of PV and 50% - 65% of ET and PMF cases; variants in CALR are found in 2-25% of ET and PMF cases; variants in MPL are found in 3% of ET and 7% of PMF cases (Barbui et al 2015).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 MPL$990.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Sensitivity

To the best of our knowledge, large deletions or duplications have not been reported in patients with CAMT or Thrombocythemia 2; missense variants and protein truncating variants are the primary causes of disease. However, in the absence of a plausible sequence variant, a test for large deletions and duplications such as gene-centric array CGH may be considered.

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Clinical Features

Congenital Amegakaryocytic Thrombocytopenia (CAMT) is a rare bone marrow failure syndrome characterized by reduced megakaryocytes, low platelet counts, and eventual pancytopenia (Muraoka et al 1997; King et al 2005). Disease onset is typically in the neonatal period or during infancy, and symptoms include easy bruising and/or bleeding episodes. Platelets are of normal size and appearance, and no physical anomalies are associated with the disease (Muraoka et al 1997). Many patients progress to pancytopenia over the first few years of life, and require bone marrow transplants. Other patients experience a transient rise in platelet counts over the first few years, before a more gradual transition to pancytopenia (King et al 2005).

In contrast to CAMT, Thrombocythemia is a myeloproliferative neoplasm (MPN) characterized by clonal expansion of megakaryocytes and increased platelet counts (Ding et al 2004). Thrombocythemia patients are at risk for bone marrow fibrosis, enhanced thrombosis, excessive bleeding, and acute leukemia transformation.


CAMT is an autosomal recessive disorder caused by inactivating variants within the MPL gene. The MPL protein acts as the cell surface receptor for thrombopoietin (Tpo) and is found on hematopoietic progenitor cells. Tpo activates the MPL receptor and acts as the main regulator of megakaryopoiesis and platelet differentiation (Kaushansky 1995; Tijssen et al 2008). Inactivating missense and nonsense variants in the MPL gene are the most frequent types of variants reported in CAMT patients; splice site variants and small deletions that result in frameshifts have also been reported. Evidence has been presented that patients with two missense pathogenic variants often have a less severe form of disease than patients with two nonsense/frameshift/splicing pathogenic variants (Germeshausen et al 2006).

Thrombocythemia 2 is associated with variants in the MPL gene that result in enhanced MPL protein signaling activity (Ding et al 2004; Lambert et al 2012; Moliterno et al 2004). Variants associated with thrombocytosis are primarily missense variants and are inherited in several ways: autosomal dominant, autosomal dominant with reduced penetrance, and autosomal recessive with a mild heterozygous phenotype (He et al 2013). Predominant variants found in patients with inherited Thrombocythemia 2 include c.317C>T (p.Pro106Leu), which is found at a high frequency among Arab patients (El-Harith et al 2009), and c.117G>T (p.Lys39Asn), aka MPL Baltimore, which is found at a high frequency in African American patients (Moliterno et al 2004). Interestingly, the c.117G>T variant was shown to dramatically decrease MPL protein expression (Moliterno et al 2004); how this variant results in thrombocytosis and not thrombocytopenia remains unclear. Acquired variants in the MPL gene are also a frequent cause of somatic MPNs.

Testing Strategy

Our DNA sequencing test involves bidirectional sequencing of all coding exons of the MPL gene. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known variants or to confirm research results.

Indications for Test

Candidates for this test are patients with symptoms consistent with CAMT, patients with increased megakaryocyte and platelet counts, and the family members of patients with known pathogenic variants.


Official Gene Symbol OMIM ID
MPL 159530
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Congenital Amegakaryocytic Thrombocytopenia AR 604498
Thrombocythemia 2 AD, AR 601977

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Genetic Counselors
  • Barbui T. et al. 2015. Blood Cancer Journal. 5: e337. PubMed ID: 26832847
  • Ding J. 2004. Blood. 103: 4198-200. PubMed ID: 14764528
  • El-Harith el-HA et al. 2009. British Journal of Haematology. 144: 185-94. PubMed ID: 19036112
  • Germeshausen M. et al. 2006. Human Mutation. 27: 296. PubMed ID: 16470591
  • He X. et al. 2013. Journal of Hematology & Oncology. 6: 11. PubMed ID: 23351976
  • Kaushansky K. 1995. Blood. 86: 419-31. PubMed ID: 7605981
  • King S. et al. 2005. British Journal of Haematology. 131: 636-44. PubMed ID: 16351641
  • Lambert M.P. et al. 2012. American Journal of Hematology. 87: 532-4. PubMed ID: 22389068
  • Moliterno A.R. et al. 2004. Proceedings of the National Academy of Sciences of the United States of America. 101: 11444-7. PubMed ID: 15269348
  • Muraoka K. et al. 1997. British Journal of Haematology. 96: 287-92. PubMed ID: 9029014
  • Tijssen M.R. et al. 2008. British Journal of Haematology. 141: 808-13. PubMed ID: 18422784
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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.

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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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