Germline DDX41 mutations define a significant entity within adult MDS/AML patients

Marie Sébert, Marie Passet, Anna Raimbault, Ramy Rahmé, Emmanuel Raffoux, Flore Sicre de Fontbrune, Marco Cerrano, Samuel Quentin, Nadia Vasquez, Mélanie Da Costa, Nicolas Boissel, Hervé Dombret, Régis Peffault de Latour, Gérard Socié, Raphaël Itzykson, Pierre Fenaux, Jean Soulier, Lionel Adès and Emmanuelle Clappier

Key Points

  • Germline DDX41 mutations are found in a significant proportion of sporadic MDS/AML patients

  • Patients with DDX41-related MDS/AML have a relatively favorable outcome


Germline DDX41 mutations are involved in familial myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). We analyzed the prevalence and characteristics of DDX41-related myeloid malignancies in an unselected cohort of 1385 patients with MDS or AML. Using targeted next-generation sequencing, we identified 28 different germline DDX41 variants in 43 unrelated patients which we classified as causal (n=21) or unknown significance (n=7) variants. We focused on the 33 patients having causal variants, representing 2.4% of our cohort. Median age was 69 years, most patients were males (79%). Only 9 patients (27%) had a family history of hematological malignancy, while 15 (46%) had personal history of cytopenias years prior to MDS/AML diagnosis. Most patients had normal karyotype (85%) and the most frequent somatic alteration was a second DDX41 mutation (79%). High-risk DDX41 MDS/AML patients treated with intensive chemotherapy (n=9) or azacitidine (n=11) had an overall response rate of 100% and 73%, respectively, with a median overall survival of 5.2 years. Our study highlights that germline DDX41 mutations are relatively common in adult MDS/AML, often without known family history, arguing for systematic screening. Salient features of DDX41-related myeloid malignancies include male preponderance, frequent pre-existing cytopenias, additional somatic DDX41 mutation and relatively good outcome.

  • Submitted April 3, 2019.
  • Revision received September 4, 2019.
  • Accepted August 7, 2019.