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

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.

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.

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.