Germline predisposition in myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) were previously thought to result solely from somatic mutations; however, familial clustering and germline genetic testing have revealed hereditary MPNs. These hereditary MPNs are one type of hereditary hematopoietic malignancy (HHM) syndrome, or hereditary blood cancer, and generally display an autosomal-dominant inheritance pattern within families. Point estimates of the prevalence of hereditary MPNs vary with testing methodology and the patient population sampled, but diagnostic yields for pathogenic/likely pathogenic variants in patients with MPNs range from 8% to 27% across all seemingly sporadic MPN cases. We discuss the history and current state of emerging knowledge regarding the genetic basis of hereditary MPNs. We use the broader HHM framework as a lens to identify and manage patients at risk for, and those who have developed, an MPN. This review discusses the selection of rigorous diagnostic assays, the need for personalized stem cell transplant care, and the lack of "precision" therapies for hereditary MPNs. Finally, we appraise hereditary MPNs in the context of existing criteria for genetic testing and discuss evidence pertaining to the potential benefits of universal germline genetic testing for patients with MPNs more broadly.