DDX41 is a multifunctional DEAD-box helicase that plays critical roles in innate immunity and hematopoietic homeostasis. The protein functions as a DNA sensor in the cGAS-STING pathway, utilizing ATP-dependent DNA-unwinding and ATP-independent strand-annealing activities to regulate dsDNA homeostasis and activate type I interferon responses upon DNA virus infection 1. DDX41 also participates in pre-mRNA splicing, RNA processing, and ribosome biogenesis 2. Germline DDX41 variants represent the most common cause of inherited predisposition to adult myeloid neoplasms, particularly myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) 34. These pathogenic variants confer negligible risk until age 40, but risk rapidly increases to 49% by age 90, with male predominance 5. DDX41-mutated myeloid neoplasms constitute a distinct clinical entity characterized by favorable outcomes, unique comutation patterns, and resistance to typically poor prognostic factors like TP53 mutations 56. Patients show excellent treatment responses, with overall survival of 49-71 months, and particularly benefit from venetoclax-based therapies 6. The disease demonstrates biallelic inactivation in 50% of germline carriers through acquisition of somatic DDX41 mutations 2.