The landscape of DDX41 mutations in blood diseases and the impact of donor-derived DDX41 variants on transplantation outcome

● Missense mutations P258L/Y259C are identified as the predominant Chinese-specific germline DDX41 variants. ● Pre-transplant DDX41 screening (VUS vs. P/LP) is recommended in related donors for better clinical outcomes. Germline variants of DDX41 were broadly investigated in myeloid neoplasms (MNs), while there is a lack of a larger cohort of Chinese patients report, and impact of donor-derived DDX41 variants on transplant outcomes has not been fully explored. We retrospectively analyzed 460 patients carrying DDX41 variants among 41 290 individuals. Although most of patients (65%) were diagnosed with MNs (mostly MDS/AML), other rarer diseases, such as AA, ALL, and lymphoma, can occur. A total of 417 germline and 262 somatic DDX41 variants were identified. The predominant pathogenic/likely pathogenic (P/LP) germline variants were P258L (26%) and Y259C (20%), followed by loss-of-function variants (25%) and c.935+4A>T (5%), which can cause aberrant intron retention. The most common somatic variants were R525H (53%), then G530D (7%) and T227M (4%). Germline variants in MNs were more often P/LP than in AA or ALL. GO (germline only) and GS (germline+somatic) mutations were distinctly distributed among diseases. Among thirteen donors included in this cohort, nine underwent transplantation. Four out of five recipients with donor-derived DDX41 -VUS variants continued to be in complete remission at 18 or 19 months after transplantation, compared to two out of four patients with donor-derived DDX41 -P/LP variants. For the first time, this study identified P258L/Y259C as predominant Chinese-specific germline DDX41 variants, expanding disease spectrum to include non-myeloid disorders, and established GS genotype as a key biomarker for myeloid malignancies. In addition, our results suggested that pre-transplant DDX41 germline screening in related donors may be beneficial for mitigating donor-derived leukemia and achieving better clinical outcomes.