AUTHOR=Bannon Sarah A. , Routbort Mark J. , Montalban-Bravo Guillermo , Mehta Rohtesh S. , Jelloul Fatima Zahra , Takahashi Koichi , Daver Naval , Oran Betul , Pemmaraju Naveen , Borthakur Gautam , Naqvi Kiran , Issa Ghayas , Sasaki Koji , Alvarado Yesid , Kadia Tapan M. , Konopleva Marina , Shamanna Rashmi Kanagal , Khoury Joseph D. , Ravandi Farhad , Champlin Richard , Kantarjian Hagop M. , Bhalla Kapil , Garcia-Manero Guillermo , Patel Keyur P. , DiNardo Courtney D. TITLE=Next-Generation Sequencing of DDX41 in Myeloid Neoplasms Leads to Increased Detection of Germline Alterations JOURNAL=Frontiers in Oncology VOLUME=10 YEAR=2021 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.582213 DOI=10.3389/fonc.2020.582213 ISSN=2234-943X 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.