Germline predisposition in myeloproliferative neoplasms

Area of Science:

• Hematology
• Genetics
• Oncology

Background:

• Myeloproliferative neoplasms (MPNs) were traditionally viewed as solely somatic mutations.
• Familial clustering and germline genetic testing have identified hereditary MPNs, a subset of hereditary hematopoietic malignancy (HHM) syndromes.
• These conditions typically follow an autosomal-dominant inheritance pattern.

Purpose of the Study:

• To review the evolving understanding of the genetic basis of hereditary MPNs.
• To discuss the application of the HHM framework for patient identification and management.
• To evaluate diagnostic assays, personalized stem cell transplant approaches, and precision therapies for hereditary MPNs.

Main Methods:

• Literature review focusing on genetic testing, inheritance patterns, and clinical management of hereditary MPNs.
• Analysis of diagnostic yields for pathogenic/likely pathogenic variants in MPN patients.
• Appraisal of current genetic testing criteria and evidence for universal germline testing.

Main Results:

• Hereditary MPNs are a significant subtype of MPNs, with pathogenic variants found in 8%–27% of seemingly sporadic cases.
• Germline genetic testing is crucial for identifying individuals and families at risk.
• Current therapeutic strategies lack precision for hereditary MPNs, highlighting the need for tailored approaches.

Conclusions:

• Hereditary MPNs represent an important clinical entity requiring specific diagnostic and management strategies.
• The HHM framework aids in risk stratification and patient care.
• Further research into universal germline genetic testing for MPN patients may improve outcomes.