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

<b>Background:</b><i>DDX41</i> 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 <i>DDX41</i> variants in Korean patients with hematologic malignancies, including the patterns of co-occurring somatic variants. <b>Methods:</b> We retrospectively reviewed 716 patients with hematologic malignancies who underwent targeted next-generation sequencing. In patients with germline <i>DDX41</i> variants, clinicopathologic features, co-occurring variants, variant allele frequency (VAF) distributions, and survival were analyzed. <b>Results:</b><i>DDX41</i> 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 <i>DDX41</i> 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 (<i>p</i> = 0.025). The most common germline <i>DDX41</i> 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 (<i>p</i> = 0.002). Somatic <i>DDX41</i> variants occurred in 63.6% of patients with germline <i>DDX41</i> variants, with R525H being the most frequent (48%), while non-<i>DDX41</i> somatic variants were detected in 78.8% of patients, most commonly involving <i>ASXL1</i>, <i>DNMT3A</i>, <i>SRSF2</i>, and <i>TET2</i>, which appeared at lower VAFs, suggesting late acquisition. <b>Conclusions:</b> This study demonstrates ethnic-specific <i>DDX41</i> 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 <i>DDX41</i>-associated myeloid neoplasms.