Clinical and Molecular Spectrum of DDX41 Variants in Korean Patients with Hematologic Malignancies

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Abstract
Background: DDX41 is one of the most frequent adult-onset myeloid neoplasm predisposition gene, yet its biology remains incompletely defined. This study investigated the frequency, spectrum, and clinical characteristics of DDX41 variants in Korean patients with hematologic malignancies, including the patterns of co-occurring somatic variants. Methods: We retrospectively reviewed 716 patients with hematologic malignancies who underwent targeted next-generation sequencing. In patients with germline DDX41 variants, clinicopathologic features, co-occurring variants, variant allele frequency (VAF) distributions, and survival were analyzed. Results:DDX41 variants were identified in 34/716 patients (4.7%), including 33 germline carriers (4.6%), occurring most frequently in AML (6.2%) and MDS (11.1%). Patients with germline DDX41 variants had a median age of 68 years, were predominantly male (69.7%), and commonly had normal karyotypes (72.7%), with similar features in AML and MDS except for lower platelet counts in AML (p = 0.025). The most common germline DDX41 variants were Y259C (20.6%), A500fs (14.7%), E7* (11.8%), V152G (11.8%), and D139G (8.8%), with null variants predominating in AML and missense variants in MDS (p = 0.002). Somatic DDX41 variants occurred in 63.6% of patients with germline DDX41 variants, with R525H being the most frequent (48%), while non-DDX41 somatic variants were detected in 78.8% of patients, most commonly involving ASXL1, DNMT3A, SRSF2, and TET2, which appeared at lower VAFs, suggesting late acquisition. Conclusions: This study demonstrates ethnic-specific DDX41 variant patterns in Korean myeloid neoplasm patients, with biallelic alterations potentially involved in early leukemogenesis. These findings provide further insight into the unique features of DDX41-associated myeloid neoplasms.
Funding Information
  • National Research Foundation of Korea (RS-2025-00519514)

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