About this condition
Leukemia — Hereditary & Familial MDS-AML
Hereditary predisposition to myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) is increasingly recognized as a distinct clinical entity. The WHO and ICC classifications now include 'myeloid neoplasms with germline predisposition' as a formal category. Key genes include GATA2 (haploinsufficiency causing immunodeficiency, lymphedema, and evolution to MDS/AML), DDX41 (the most common germline MDS/AML predisposition gene in adults, often with late onset), RUNX1 (familial platelet disorder with predisposition to AML), CEBPA (familial AML with high penetrance), ETV6 (thrombocytopenia with predisposition to ALL and MDS), and ANKRD26 (thrombocytopenia with MDS/AML risk).
The most critical clinical implication of hereditary MDS/AML diagnosis is bone marrow transplant (HSCT) donor selection. When a patient with MDS/AML requires HSCT, related donors are the preferred source — but if the MDS/AML has a germline cause, siblings have a 50% chance of carrying the same predisposition variant. Using a carrier sibling as a donor risks transplanting a marrow that will itself develop MDS/AML. Multiple cases of donor-derived MDS/AML have been reported when germline predisposition was not recognized. Current NCCN guidelines recommend germline testing of all MDS/AML patients before HSCT to guide donor selection.
GATA2 deficiency deserves special attention — it presents as a syndrome of immunodeficiency (MonoMAC — monocytopenia and mycobacterial infection, or DCML deficiency), lymphedema, and pulmonary alveolar proteinosis BEFORE progressing to MDS/AML. Recognition of the immunodeficiency phenotype enables proactive bone marrow monitoring and pre-emptive HSCT before acute leukemia develops. DDX41 is distinctive for its late onset — often presenting as MDS/AML in the 6th-7th decade, mimicking 'sporadic' MDS. Up to 5% of adult MDS/AML may have germline DDX41 variants.
DDX41 germline variants cause ~5% of adult MDS/AML — often presenting after age 60 and mimicking sporadic disease. Without germline testing, these cases are never identified as hereditary, and at-risk family members remain unscreened.
- Gene locus
- GATA2 (3q21.3), DDX41 (5q35.3), RUNX1 (21q22.12), CEBPA (19q13.11), ETV6 (12p13.2), ANKRD26 (10p12.1), SAMD9 (7q21.2)
