Germline DDX41 mutations define a significant entity within adult MDS/AML patients | Aplastic Anemia and MDS International Foundation (AAMDSIF) Return to top.

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

Journal Title: 
Primary Author: 
Sebert M
Sébert M, Passet M, Raimbault A, Rahmé R, Raffoux E, Sicre de Fontbrune F, Cerrano M, Quentin S, Vasquez N, Da Costa M, Boissel N, Dombret H, Peffault de Latour R, Socié G, Itzykson R, Fenaux P, Soulier J, Adès L, Clappier E
Original Publication Date: 
Wednesday, September 4, 2019
Bone Marrow Disease(s): 

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.