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

Blood. 2019 Oct 24;134(17):1441-1444. doi: 10.1182/blood.2019000909.


Germline DDX41 mutations are involved in familial myelodysplastic syndromes (MDSs) and acute myeloid leukemias (AMLs). 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. The median age was 69 years; most patients were men (79%). Only 9 patients (27%) had a family history of hematological malignancy, and 15 (46%) had a personal history of cytopenia years before MDS/AML diagnosis. Most patients had a 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% or 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 preexisting cytopenia, additional somatic DDX41 mutation, and relatively good outcome.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Cohort Studies
  • DEAD-box RNA Helicases / genetics*
  • Female
  • Germ-Line Mutation
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Male
  • Middle Aged
  • Myelodysplastic Syndromes / genetics*


  • DDX41 protein, human
  • DEAD-box RNA Helicases