Abstract
Previously considered rare, inherited hematologic malignancies are increasingly identified. Germline mutations in the RNA helicase DDX41 predispose to increased lifetime risks of myeloid neoplasms with disease often occurring later in life which presents challenges for germline recognition. To improve identification of germline DDX41, individuals presenting with ≥1 DDX41 alteration on an institutional MDS/AML next-generation sequencing based panel with at least one at >40% variant allele frequency were flagged for review and genetic counseling referral. Of 5,801 individuals, 90 (1.5%) had ≥1 DDX41 mutation(s) identified. Thirty-eight (42%) patients with a median age of 66 years were referred for genetic counseling; thirty-one were male (81.5%). Thirty-five (92%) referred patients elected to pursue germline evaluation and in 33/35 (94%) a germline DDX41 variant was confirmed. Twenty-two patients (66%) with germline variants reported antecedent cytopenias, seven (21%) had a prior history of malignancy, and twenty-seven (82%) reported a family history of cancer. Predictive genetic testing for healthy family members under consideration as stem cell transplant donors was successfully performed in 11 family members, taking an average of 15 days. Near-heterozygous DDX41 mutations identified on next-generation sequencing, particularly nonsense/frameshift variants or those at recurrent germline “hot spots” are highly suggestive of a germline mutation. Next-generation sequencing screening is a feasible tool to screen unselected myeloid neoplasms for germline DDX41 mutations, enabling timely and appropriate care.
Highlights
Over the past decade, identification of and clinical testing for inherited predispositions to hematologic malignancies has emerged as one of the fastest growing areas of cancer genetics
Thirty-eight out of 90 (42%) individuals with DDX41-mutated hematologic neoplasms at near-heterozygous frequency were referred for genetic counseling and offered germline testing
Presenting myeloid malignancies were varied including 18 (47%) with MDS, 15 (39%) with AML, three (7%) with therapy-related myeloid neoplasm (t-MN), one (3%) with chronic lymphocytic
Summary
Identification of and clinical testing for inherited predispositions to hematologic malignancies has emerged as one of the fastest growing areas of cancer genetics. The average age of MDS/AML onset in mutation carriers is notably older at 65 years, than in many cancer predisposition syndromes and overlaps with the general population of sporadic MDS/AML diagnoses [7, 9, 10]. This low penetrance often results in a limited or absent family history, which prevents identifying patients who might otherwise be flagged for genetic evaluation based on family history criteria. Lenalidomide has been suggested as an effective treatment strategy for myeloid malignancies with DDX41 mutations [and without del(5q)] based on case reports and retrospective analyses [13, 14]
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