The most prevalent mutations predisposing to acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) in adults are DDX41 variations. However, the causal variant (CV) landscape and clinical spectrum of hematologic malignancies (HMs) remained unknown.

Among 9,821 unrelated individuals, researchers examined the genomic profiles of 176 patients with HM who carried 82 different germline DDX41 mutations. They discovered criteria that distinguished 116 individuals with HM with CV from 60 patients with HM with a variation of uncertain significance (VUS) using the proposed DDX41-specific variant classification: an older age (median 69 years), male predominance (74% in CV vs. 60% in VUS, P=.03), frequent concurrent somatic DDX41 variants (79% in CV vs. 5% in VUS, P=.0001), a lower somatic mutation burden (1.4±0.1 in CV vs. 2.9±0.04 in VUS, P=.012), near exclusion of canonical recurrent genetic abnormalities including mutations in NPM1, CEBA, and FLT3 in AML and favorable overall survival (OS) in patients with AML/MDS. In addition, in patients with AML/MDS, the improved OS was established independent of blast count, aberrant karyotypes, and contemporaneous variations, including TP53, regardless of patient sex, age, or germline CV, suggesting that germline DDX41 variants define a separate clinical entity.

Furthermore, DDX41 CV was used to link unrelated individuals with B-cell lymphoma and myeloproliferative neoplasm, broadening the known illness range. This report highlights the critical need for gene-specific diagnostic and clinical care guidelines by describing the CV landscape, broadening the phenotypic spectrum in unrelated DDX41-mutated individuals.