Submission Details

The THPO gene encodes the ligand for MPL, thrombopoietin, a hematopoietic growth factor that regulates the development of megakaryocytes and platelets as well as the self-renewal of hematopoietic stem cells.

LUMPING AND SPLITTING CONSIDERATIONS:

Thrombocythemia 1; OMIM: 187950; MONDO:0008554 Thrombocytopenia, congenital amegakaryocytic; OMIM: 604498; MONDO: 0011469

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms (loss of function vs gain of function), inheritance pattern (autosomal dominant vs autosomal recessive) and phenotypic variability (thrombocythemia vs thrombocytopenia) between these two phenotypes thus the disorders have been split.

THPO was first reported in relation to congenital amegakaryocytic thrombocytopenia inherited in an autosomal-recessive manner in 2013 (Dasouki et al., PMID: 24085763) in a Micronesian family.

Nonsense, missense and frameshift variants have been reported in humans thus far. The disease mechanism is loss of function. Evidence supporting this gene-disease relationship includes genetic evidence (case-level data) and experimental evidence (biochemical functions, protein interaction and animal model).

Summary of Case Level Data: 4.4 points: Variants in this gene have been reported in at least 5 probands in 3 publications (PMIDs: 29191945, 24085763, 28559357). Five additional individuals from two publications (PMIDs: 28466964, 32150607) have been noted to have monoallelic loss of function variants. These individuals have been added to this gene-disease record, but not scored. The H/T GCEP is aware that there is published (5 cases) and unpublished (at least one individual with heterozygous nonsense variant, along with GFI1b C168F variant) evidence to suggest that there may be a semi-dominant mode of inheritance for the thrombocytopneia phenotype caused by THPO variants as heterozygous carrier relatives of probands with homozygous alterations also display reduced platelet counts (PMIDs: 24085763, 29191945); however, there has not been overwhelming evidence at this time to confirm that THPO-associated thrombocytopenia is indeed inherited in a semi-dominant manner.

Summary of Experimental Data: 3.5 points: This gene-disease relationship is supported by in vitro functional assays. THPO is involved in megakaryopoiesis and thrombopoiesis, and loss of function variants in THPO lead to decrease in platelet counts (PMID: 23594368). Chen et al. showed that THPO physically interacts with MPL. (PMID: 20529857). A knock-out mouse model was generated by Sauvage et al, wherein homozygous KO mice recapitulated the thrombocytopenia phenotype while the heterozygous mice showed a significant reduction in platelet counts (PMID: 8627177)

In summary, the level of evidence to support the gene-disease relationship of THPO and autosomal recessive congenital amegakaryocytic thrombocytopenia is moderate. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

This classification was approved by the ClinGen Hemostasis Thrombosis Working Group on March 24, 2022 (SOP Version 8).