The Genetic Landscape of DDX41 Gene Variants in Myeloid Neoplasms: A Large Single-Center Cohort Study from China
Authors: Qin Li , Jia Yujiao , Wang Haoxu , Han Xiaoxue , Qu Shiqiang , Wang Huijun , Sun Qi , Li Chengwen , Xiao Jigang , Wei Hui , Mi Yingchang , Wang Jianxiang , Xiao Zhijian 
Published: December 2024

Background
Germline variants in DDX41 are the most prevalent mutations predisposition to myeloid neoplasms (MN), including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Up to date, demographic distribution of the causal variant landscape of DDX41 and clinical features has been reported, except in Chinese patients that are largely unknown.
Objective
The aim of this study is to assess the genetic landscape of DDX41 as well as clinical features in Chinese patients with hematologic malignancies.
Methods
Next-generation sequencing (NGS) data were retrospectively analyzed for patients referred to our center from Feb 2020 to Nov 2023.
Results
A total of 460 patients were found to harbor DDX41 mutations among 35,934 individuals referred to our center. Among 413 patients that carries at least one germline DDX41 variants, 61 distinct pathogenic/likely pathogenic (P/LP) variants and 64 distinct variants of unknown significance (VUS) were identified. Among these variants 20 were verified as germline. The most prevalent P/LP variants were P258L, Y259C and c.935+4A&gt;T, accounting for &gt;50% of deleterious variants in our cohort, suggesting these are founder variants in Chinese population, while the most common VUS variants were K187R, R8W and D139G that accounts for 34% of VUS variants. The c.935+4A&gt;T variant led to two alternative splicing variants in intron 9 and thus resulted in intronic retention and protein elongation. We also identified the features of patients with DDX41 variants: an older age (median age: 60 years) and male predominance (male : female = 1 : 0.51). The clinical diagnosis of these patients were: MDS (145 pts), AML (68 pts), AA (46 pts), MPN (16 pts), ALL (14 pts), others were CCUS, CLL, lymphoma, MDS/MPN, MM, etc. There were 13 donors of hematopoietic stem cell tranplantation (HSCT) were found to carry DDX41 mutations. The mutational pattern of DDX41 were different among diseases: 71% of MDS and 53% of AML patients carried both germline and somatic DDX41 mutations, while &gt;83% of AA, MPN and ALL patients carried only germline DDX41 variants. Moreover, most of germline variants in MDS and AML patients were P/LP, compared with most of VUS in AA and ALL patients, underlying a pivotal linkage of this DEAD-box RNA helicase in an increased risk of myeloid neoplasm development. The mutational spectrum of MDS and AML patients were similar: most prevalent in ASXL1, TP53, DNMT3A, SRSF2, CUX1 and TET2, while FLT3, CEBPA and WT1 mutations were more prominent in AML. Clonal evolution were also analyzed and showed that somatic DDX41 variants could be augmented/appeared or diminished/disappeared upon beginning of or changes in chemotherapy.
Conclusion
Collectively, our study unravels the genetic landscape and important role of DDX41 gene variants in myeloid neoplasms and outlines the likelihood of P258L and Y259C as founder variants in Chinese population, as well as clonal evolution in MN patients.
Keywords: DDX41, NGS, myeloid neoplasm, genetic landscape, clonal evolution
Disclosures: L Qin, Y Jia, HX Wang, S Qu, HJ Wang, Q Sun, C Li, J Xiao, H Wei, Y Mi, J Wang, Z Xiao have no interest to disclose. X Han is employee of Tianjin Kingmed Center for Clinical Laboratory.