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Familial thrombocytosis is an autosomal dominant myeloproliferative disorder characterized by lifelong, mild to moderate elevation of platelet counts. Germline mutations in the Janus kinase 2 gene (JAK2) have been identified as a key cause of this inherited thrombocytosis phenotype, designated MONDO:0019111.
Affected individuals in several kindreds harbor heterozygous JAK2 missense variants that co-segregate with thrombocytosis, with no variant detected in unaffected relatives ([PMID:26413420]). In a detailed study of two unrelated families, novel germline variants R867Q and the cis-paired S755R/R938Q were each associated with persistent elevated platelet counts, and were absent in tested family members without thrombocytosis (2 families ([PMID:24398328])).
The variant spectrum includes missense changes in both the pseudokinase (JH2) and kinase (JH1) domains. For example, c.2813G>A (p.Arg938Gln) was identified in one kindred with familial thrombocytosis. All reported variants were absent from population controls and predicted to affect regulatory domains of JAK2.
Functional studies demonstrate that these germline variants confer a gain-of-function mechanism: Ba/F3-MPL cells expressing JAK2 R867Q or S755R/R938Q exhibit spontaneous proliferation and thrombopoietin-independent STAT1 phosphorylation. Mutant proteins show prolonged half-life, increased HSP90 chaperone binding, and enhanced MPL cell-surface expression ([PMID:24398328], [PMID:26413420]).
No conflicting reports have been described, and the collective genetic and experimental findings provide concordant evidence of pathogenicity. Additional large-scale segregation studies could further reinforce the association.
Key Take-home: Germline JAK2 testing is recommended in families with unexplained inherited thrombocytosis to confirm diagnosis, inform risk stratification, and guide management.
Gene–Disease AssociationModerate2 families with heterozygous JAK2 variants segregating with thrombocytosis ([PMID:24398328]); functional concordance in vitro Genetic EvidenceModerateNovel germline JAK2 missense variants identified in 2 unrelated kindreds with autosomal dominant inheritance and clear absence in unaffected relatives Functional EvidenceModerateBa/F3-MPL cell assays show spontaneous proliferation, TPO-independent STAT1 phosphorylation, and increased protein stability for R867Q and S755R/R938Q variants |