Introduction: Germline predispositions to hematologic malignancies were historically thought to be rare; however growing awareness has raised clinical challenges regarding how to identify, test, and manage these patients. Germline mutations in the gene DDX41 predispose to moderately increased lifetime risks of MDS and AML with a later age of onset. Optimal clinical care of these patients relies on identifying germline mutations and innovative strategies are needed to improve clinical detection.

Methods: 1,262 individuals with myeloid malignancies underwent next-generation sequencing (NGS)-based molecular sequencing of DDX41. Individuals identified to have ≥1 DDX41 alterations present at >40% variant allele frequency (VAF) in the bone marrow were flagged for potential referral to genetic counseling (GC). All individuals referred for GC underwent standard genetic counseling evaluation and were offered DDX41 germline analysis on cultured skin fibroblasts.

Results: Of 1,262 individuals, 32 (2.5%) were identified to have ≥1 somatic DDX41 mutation(s). Fourteen (44%) were referred for GC and germline confirmation testing. Eleven patients were male (78.5%) and 13/14 (93%) were Caucasian. Average age at diagnosis of myeloid neoplasm was 65 years (range 53-77 years). Fifty-seven percent (8/14) individuals were diagnosed with AML, 6/14 presented with MDS, including therapy-related MDS. 12/14 patients had diploid cytogenetics at presentation. A second somatic DDX41 mutation (biallelic) was identified in 10/14 (71%). There were no other significantly recurrent concomitant somatic mutations. Thirteen patients underwent germline evaluation and 12/13 (92%) were confirmed to have a germline DDX41 mutation. Six individuals underwent hematopoietic stem cell transplantation (SCT); five from a matched related donor, and in four cases, the related donor was negative for the familial DDX41 mutation. Six patients (43%) reported antecedent cytopenias: five with leukopenia and one with anemia. Five patients had a prior history of malignancy: three with prostate cancer, one with Non-Hodgkin's lymphoma and melanoma, and one with MGUS. 13/14 (93%) patients reported a family history of cancer, six (43%) of which included hematologic malignancies and/or cytopenias. From the 12 DDX41 germline-positive patients, 11 unaffected relatives underwent genetic testing. Four (36%) tested positive for the familial DDX41 mutation and seven (64%) tested negative.

Conclusions: The detection of somatic DDX41 mutations at near-heterozygous frequencies on NGS panel testing is highly suggestive of a germline mutation and germline testing is strongly recommended. Our data validates existing reports in DDX41 germline patients including primarily high grade myeloid neoplasms, diploid cytogenetics, and later age at diagnosis. Interestingly nearly half of our patients had antecedent cytopenias, most often leukopenia. NGS screening for DDX41 mutations through multi-disciplinary collaboration is a useful and feasible tool to screen unselected myeloid neoplasm patients for high likelihood of germline DDX41 mutations enabling timely and appropriate care of these patients.


Daver:Novartis: Consultancy; Incyte: Research Funding; Pfizer: Consultancy; ImmunoGen: Consultancy; Pfizer: Research Funding; Sunesis: Consultancy; Alexion: Consultancy; Novartis: Research Funding; Sunesis: Research Funding; Kiromic: Research Funding; Karyopharm: Research Funding; ARIAD: Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Incyte: Consultancy; Otsuka: Consultancy; Karyopharm: Consultancy. Oran:AROG pharmaceuticals: Research Funding; Celgene: Consultancy, Research Funding; ASTEX: Research Funding. Kadia:Abbvie: Consultancy; Abbvie: Consultancy; Jazz: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Research Funding; Celgene: Research Funding; BMS: Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Novartis: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy. DiNardo:Karyopharm: Honoraria; Celgene: Honoraria; Bayer: Honoraria; Abbvie: Honoraria; Medimmune: Honoraria; Agios: Consultancy.

Author notes


Asterisk with author names denotes non-ASH members.