Germline DDX41 mutations in myeloid neoplasms: a comprehensive review

DEAD-box helicase 41 (DDX41)-associated myeloid neoplasms represent a distinct hereditary cancer syndrome and have emerged as the most common form of genetic predisposition to adult-onset hematologic malignancies, accounting for 3–5% of adults with myelodysplastic syndrome and acute myeloid leukemia. DDX41 is a multifunctional DEAD-box RNA helicase that plays essential roles in pre-mRNA splicing, ribosome biogenesis, and innate immune regulation. Pathogenic germline variants predominantly cluster within the N-terminal region, whereas somatic second-hit mutations are concentrated in the C-terminal helicase domain. The characteristic “two-hit” model involves a germline loss-of-function mutation followed by a somatic variant—most commonly p.R525H—leading to malignant transformation. This process occurs through defective small nucleolar RNA processing, impaired ribosome assembly, erythropoietic abnormalities, and R-loop–mediated DNA damage. Clinically, the phenotype is consistent and characterized by late-onset disease in the sixth to seventh decades of life, a strong male predominance, hypocellular bone marrow, and normal cytogenetics. Despite these distinctive features, affected individuals generally exhibit favorable treatment responses and outcomes compared with sporadic cases. An important clinical consideration in DDX41-associated disease management is the planning of allogeneic hematopoietic cell transplantation, where genetic screening for DDX41 variants among potential related donors is essential. Future investigations should aim to elucidate the molecular mechanisms underlying DDX41-driven leukemogenesis, refine surveillance strategies, and develop targeted therapeutic approaches.