1. The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants
- Author
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Aline Renneville, Judith C. W. Marsh, Carolyn Owen, Andrew Green, Rogier Mous, Jude Fitzgibbon, Andrew R. Hallahan, David Taussig, Jun Wang, Josep F. Nomdedeu, Ahad F. Al Seraihi, Mark Layton, Nikolas Pontikos, Doris Steinemann, Kim Reay, Vincent Plagnol, Rachel Protheroe, Tim Ripperger, Susanna Akiki, Joanne Mason, Upal Hossain, Henrik Hjorth-Hansen, Anne Uyttebroeck, Amanda J. Walne, Nigel H. Russell, Jenna Alnajar, Nele Hug, Claude Preudhomme, Jamie Cavenagh, Findlay Bewicke-Copley, Csaba Bödör, Kiran Tawana, Adrian Bloor, Cynthia L. Toze, Alicia Ellison, Paula Page, Gabriela Sciuccati, Inderjeet Dokal, Tom Vulliamy, John K. Wu, Jiri Pavlu, Peter Vandenberghe, Hemanth Tummala, Elspeth Payne, Michael L. Barnett, David T. Bowen, Brigitte Schlegelberger, Priyanka Mehta, Ana Rio-Machin, Alison Male, Shirleny Cardoso, Hannah Armes, Anand Saggar, Sarah Lawson, Nuria Pujol-Moix, Javier F. Cáceres, Pierre Fenaux, and Sally Killick
- Subjects
0301 basic medicine ,Myeloid ,Adenosine Deaminase ,Vesicular Transport Proteins ,General Physics and Astronomy ,DYSKERATOSIS-CONGENITA ,Whole Exome Sequencing ,Cohort Studies ,0302 clinical medicine ,hemic and lymphatic diseases ,CEBPA ,Cancer genomics ,RUNX1 MUTATIONS ,lcsh:Science ,Exome sequencing ,MYELODYSPLASTIC SYNDROME ,Genetics ,Multidisciplinary ,Receptors, Interleukin-17 ,Myeloid leukemia ,SAMD9L MUTATIONS CAUSE ,Pedigree ,Multidisciplinary Sciences ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Science & Technology - Other Topics ,RNA Helicases ,Platelet disorder ,Science ,LINE ,ACUTE MYELOID-LEUKEMIA ,Platelet Membrane Glycoproteins ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Acute myeloid leukaemia ,03 medical and health sciences ,Germline mutation ,PLATELET DISORDER ,Exome Sequencing ,medicine ,Humans ,MECHANISTIC INSIGHTS ,Germ-Line Mutation ,Adaptor Proteins, Signal Transducing ,Science & Technology ,Perforin ,Myelodysplastic syndromes ,General Chemistry ,Axonemal Dyneins ,medicine.disease ,Nonsense Mediated mRNA Decay ,SELF-RENEWAL ,030104 developmental biology ,Myelodysplastic Syndromes ,lcsh:Q - Abstract
The 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., Familial myeloid malignancies have recently been classified as separate disease entities. Here, using whole-exome sequencing of affected pedigrees - the authors highlight genetic variants associated with these conditions.
- Published
- 2020