Myeloid neoplasms (MNs) with germline DDX41 variants were confirmed to be a unique subtype of MNs, according to research published in Blood. Researchers conducted a retrospective study to comprehensively characterize DDX41 mutations in a multinational cohort of patients with MNs enrolled at 56 institutes or projects across 7 countries.

A total of 9082 patients with MNs who previously underwent genetic analysis were included in the study. Patients had a median age of 65 years (range, 1-94). The researchers identified 557 pathogenic/likely-pathogenic (P/LP) DDX41 germline variants and/or somatic mutationsin 346 patients (3.8%). Together with data from first-degree relatives of patients, the team determined 328 variants were germline variants and 229 were somatic mutations.

The researchers found P/LP DDX41 germline variants explained approximately 80% of the predisposition for MNs in adult patients. They discovered these risk variants were enriched by 10-fold among Japanese patients with MNs compared with the general population of Japan. They also discovered the enrichment of DDX41 risk alleles was more prominent in men (odds ratio [OR], 20.7; 95% CI, 10.9-41.0) than women (OR, 5.00; 95% CI, 2.27-10.9). The study revealed P/LP DDX41 variants conferred a life-time risk of developing MNs of approximately 50%.

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The researchers also observed that patients with myelodysplastic syndromes with DDX41 truncating variants rapidly progressed to acute myeloid leukemia (AML); in patients with P/LP germline non-truncating variants or with somatic mutations alone, they found progression to AML was no faster than that observed in DDX41-WT cases.

“These findings highlight the relevance of correctly recognizing DDX41-mutation status in the management of patients with MN,” concluded the researchers. “[They also] emphasize the need for recognition of the importance of germline predisposition to MNs, now feasible thanks to the more widespread adaptation of germline genetic testing in individuals with MNs and their family members.”

The primary limitation of the study was retrospective design.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of authors’ disclosures. 


Makishima H, Saiki R, Nannya Y, et al. Germ line DDX41 mutations define a unique subtype of myeloid neoplasms. Blood. 2023;141(5):534-549. doi:10.1182/blood.2022018221