The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants
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Published:2020-02-25
Issue:1
Volume:11
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Rio-Machin AnaORCID, Vulliamy Tom, Hug Nele, Walne Amanda, Tawana Kiran, Cardoso Shirleny, Ellison AliciaORCID, Pontikos Nikolas, Wang JunORCID, Tummala Hemanth, Al Seraihi Ahad Fahad H., Alnajar Jenna, Bewicke-Copley FindlayORCID, Armes Hannah, Barnett Michael, Bloor Adrian, Bödör CsabaORCID, Bowen David, Fenaux Pierre, Green Andrew, Hallahan Andrew, Hjorth-Hansen HenrikORCID, Hossain Upal, Killick Sally, Lawson Sarah, Layton Mark, Male Alison M., Marsh Judith, Mehta Priyanka, Mous Rogier, Nomdedéu Josep F.ORCID, Owen Carolyn, Pavlu JiriORCID, Payne Elspeth M.ORCID, Protheroe Rachel E., Preudhomme Claude, Pujol-Moix Nuria, Renneville Aline, Russell Nigel, Saggar Anand, Sciuccati Gabriela, Taussig David, Toze Cynthia L., Uyttebroeck AnneORCID, Vandenberghe PeterORCID, Schlegelberger Brigitte, Ripperger Tim, Steinemann DorisORCID, Wu John, Mason Joanne, Page Paula, Akiki Susanna, Reay Kim, Cavenagh Jamie D., Plagnol VincentORCID, Caceres Javier F.ORCID, Fitzgibbon Jude, Dokal Inderjeet
Abstract
AbstractThe inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference78 articles.
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