Germline Mutation

Background: Hereditary hematopoietic malignancy (HHM) syndromes are a group of inherited disorders that raises the risk of blood cancers. Many people with HHMs have changes in a gene (DDX41) that makes it more likely that they will develop myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), or other cancers. This natural history study will explore the link between HHM syndromes and these diseases. Objective: To study the link between HHM and MDS/AML. Eligibility: People aged 1 month and older with HHM. Relatives with HHM are also needed. Design: Participants aged 3 years and older will have 1 initial clinic visit with the option to follow-up annually. They will undergo these procedures: They will have a physical exam with blood and urine tests. They may give samples of saliva, stool, nails, and skin. Their ability to do normal activities will be reviewed. Some may have a bone marrow biopsy: A tissue sample will be drawn from inside a bone. They may answer questions about their health and family medical history. Participants younger than 3 years, and those who cannot come to the clinic, will be contacted by phone or email. Their samples may be collected locally and sent to researchers. For participants who have changes in their DDX41 gene: Researchers will contact them or their primary care provider once a year for 10 years. Researchers will check on participants health and collect any new test results. Some may be asked to send new samples. Participants who do not have changes in their DDX41 gene may be contacted yearly, or less often, for 10 years. Some participants may be asked to return to the clinic if needed.

The classic Ph-negative myeloproliferative neoplasms (MPN) are a group of clonal hematopoietic disorders caused by a dysregulated JAK/STAT signal transduction because of acquired somatic mutations of JAK2, CALR or MPL genes. They are sporadic diseases but there are several lines of evidence that support the role of germline factors in the pathogenesis of MPN: the existence of familial clustering, the presence of more than one clone in some patients, the known existence of common polymorphisms that cause predisposition to MPN. In this study, we would like to define the germline predisposition to MPN.