IntroductionInheritedDDX41mutations cause familial predisposition to hematologic malignancies including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), with the majority of DDX41 mutated MDS/AMLs described to date harboring germlineDDX41and co-occurring somaticDDX41variants. DDX41-AMLs were shown to share distinguishing clinical features such as a late AML onset and an indolent disease associated with a favorable outcome. However, genotype-phenotype correlation in DDX41-MDS/AMLs remain poorly understood.MethodsHere, we studied the genetic profile, bone marrow morphology and immunophenotype of 51 patients with DDX41 mutations. We further assessed the functional impact of ten previously uncharacterizedDDX41variants of uncertain significance.ResultsOur results demonstrate that MDS/AML cases harboring twoDDX41variants share specific clinicopathologic hallmarks that are not seen in other patients with monoallelicDDX41related hematologic malignancies. We further showed that the features seen in these individuals with twoDDX41variants were concordant with biallelicDDX41disruption.DiscussionHere, we expand on previous clinicopathologic findings onDDX41mutated hematologic malignancies. Functional analyses conducted in this study unraveled previously uncharacterizedDDX41alleles and further illustrate the implication of biallelic disruption in the pathophysiology of this distinct AML entity.