The genetic landscape of germline DDX41 variants predisposing to myeloid neoplasms

Area of Science:

• Genetics and Genomics
• Hematology
• Oncology

Background:

• Germline DDX41 variants are the most common mutations associated with adult acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
• The landscape of causal variants (CV) and the full clinical spectrum of hematologic malignancies (HMs) linked to DDX41 variants remain incompletely understood.

Purpose of the Study:

• To analyze the genomic profiles of patients with HMs carrying germline DDX41 variants.
• To identify features distinguishing causal variants (CV) from variants of uncertain significance (VUS).
• To expand the understanding of the phenotypic spectrum and clinical outcomes associated with DDX41 variants.

Main Methods:

• Genomic profiling of 176 patients with HM carrying 82 distinct germline DDX41 variants from a cohort of 9821 unrelated patients.
• Classification of DDX41 variants into CV and VUS based on specific criteria.
• Comparison of clinical and genomic features between patients with CV and VUS.

Main Results:

• Identified 116 patients with HM with CV and 60 with VUS.
• Patients with CV were older, had a male predominance, and frequently presented with concurrent somatic DDX41 variants.
• CV cases showed a lower somatic mutation burden, near exclusion of canonical AML mutations (NPM1, CEBPA, FLT3), and favorable overall survival (OS) in AML/MDS, independent of other clinical factors.
• DDX41 CV was also linked to myeloproliferative neoplasms and B-cell lymphoma, expanding the disease spectrum.

Conclusions:

• Germline DDX41 variants define a distinct clinical entity in hematologic malignancies, characterized by specific genomic features and favorable survival in AML/MDS.
• The study clarifies the CV landscape and expands the phenotypic spectrum of DDX41-mutated HMs.
• Highlights the need for gene-specific diagnostic and clinical management guidelines for DDX41 variants.