JAK2 p.R564 germ line variants associated with hereditary thrombocythemia and hematologic neoplasms

The Janus kinase 2 (JAK2) V617F mutation activates the transcription pathway and has been well characterized as a driver of myeloproliferative neoplasms (MPNs). Recently, there has been a heightened interest in understanding germ line predisposition to hematologic malignancies such as MPN, including several reports of familial MPN. Here, we retrospectively analyzed medical records and data from genetic testing to describe 12 patients with germ line variants at amino acid position 564 of JAK2. This includes 3 supportive cases adding to prior literature regarding the germ line JAK2 R564Q association with hereditary thrombocythemia, as well as confirmation of JAK2 R564L as a germ line variant associated with MPN. Importantly, the symptomatic burden for many of the individuals in this series is comparable with that of individuals with the canonical V617F mutation profile. In the JAK2 R564Q cases, we noted a pattern of familial aggregation, presence of congenital thrombocythemia, and co-occurrence with hematologic neoplasms. Identification of germ line predisposition is essential for understanding the pathogenesis of disease, impact on families, and opportunities for preventive care. Continued research is essential to further characterize the penetrance of these conditions and how best to monitor, treat, and optimize management for these families.