Abstract
Objective: To enhance understanding of familial hereditary thrombocythemia (HT) associated with novel JAK2 germline mutations and improve precision diagnosis and treatment.
Methods: Whole-exome sequencing and Sanger/PCR-NGS validation of mutation sites were performed in a family with varying degrees of thrombocytosis, followed by a literature review.
Results:The proband had a 19-year history of thrombocytosis, normal spleen on physical examination, and negative results for common MPN driver gene mutations. Bone marrow smear showed 225 megakaryocytes with hypercellularity, and biopsy revealed megakaryocytes with multilobulated nuclei. Chromosomal analysis was normal. Family history indicated thrombocytosis in the father and younger sister. Sequencing identified that the proband and the elder sister inherited a JAK2 c.698T>C (p.Phe233Ser) heterozygous mutation in the FERM domain from the mother and a JAK2 c.2423T>G (p.Leu808Trp) heterozygous mutation in the Pseudo-kinase domain from the father. Both presented with orbital distension, with platelet counts fluctuating between 500–1000×10⁹/L (proband) and 400–689×10⁹/L (elder sister). The younger sister and mother carried only the JAK2 c.698T>C (p.Phe233Ser) mutation, were asymptomatic, and were incidentally found to have mildly elevated platelets (310–335×10⁹/L and 362×10⁹/L, respectively). The father, diagnosed with “cerebral hemorrhage and hypertension,” had platelets around 300×10⁹/L, peaking at 400×10⁹/L. Homology modeling predicted that the p.Phe233Ser mutation altered the side chain of residue 233, forming a new hydrogen bond with residue 229, potentially affecting protein conformation and stability. The p.Leu808Trp mutation showed no hydrogen bond changes or polarity alteration, suggesting minimal impact on conformation or stability but possible interference with autoinhibition.
Conclusion: Isolated JAK2 c.698T>C (p.Phe233Ser) or JAK2 c.2423T>G (p.Leu808Trp) germline heterozygous mutations cause platelet counts slightly above the upper limit, while co-mutation synergistically exacerbates the HT phenotype. These novel JAK2 mutations in the FERM and Pseudo-kinase domains expand the genotypic-phenotypic understanding of hereditary thrombocythemia and provide potential targets for therapy.
