Congenital Amegakaryocytic Thrombocytopenia (CAMT) and Thrombocythemia 2 via the MPL Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
7749 MPL 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
7749MPL81479 81479(x2) $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

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

Turnaround Time

18 days on average for standard orders or 13 days 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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Siwu Peng, PhD

Clinical Features and Genetics

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.

Genetics

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.

Clinical Sensitivity - Sequencing with CNV PG-Select

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).

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.

Testing Strategy

This test provides full coverage of all coding exons of the MPL gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

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. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in MPL.

Gene

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

Diseases

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

Related Tests

Name
Bleeding Disorders Panel
Thrombocytopenia Panel

Citations

  • 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

Ordering/Specimens

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


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

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