The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants

Ana Rio-Machin (), Tom Vulliamy (), Nele Hug, Amanda Walne, Kiran Tawana, Shirleny Cardoso, Alicia Ellison, Nikolas Pontikos, Jun Wang, Hemanth Tummala, Ahad Fahad H. Al Seraihi, Jenna Alnajar, Findlay Bewicke-Copley, Hannah Armes, Michael Barnett, Adrian Bloor, Csaba Bödör, David Bowen, Pierre Fenaux, Andrew Green, Andrew Hallahan, Henrik Hjorth-Hansen, Upal Hossain, Sally Killick, Sarah Lawson, Mark Layton, Alison M. Male, Judith Marsh, Priyanka Mehta, Rogier Mous, Josep F. Nomdedéu, Carolyn Owen, Jiri Pavlu, Elspeth M. Payne, Rachel E. Protheroe, Claude Preudhomme, Nuria Pujol-Moix, Aline Renneville, Nigel Russell, Anand Saggar, Gabriela Sciuccati, David Taussig, Cynthia L. Toze, Anne Uyttebroeck, Peter Vandenberghe, Brigitte Schlegelberger, Tim Ripperger, Doris Steinemann, John Wu, Joanne Mason, Paula Page, Susanna Akiki, Kim Reay, Jamie D. Cavenagh, Vincent Plagnol, Javier F. Caceres, Jude Fitzgibbon () and Inderjeet Dokal ()
Additional contact information
Ana Rio-Machin: Queen Mary University of London
Tom Vulliamy: Queen Mary University of London
Nele Hug: University of Edinburgh
Amanda Walne: Queen Mary University of London
Kiran Tawana: Addenbrooke’s Hospital
Shirleny Cardoso: Queen Mary University of London
Alicia Ellison: Queen Mary University of London
Nikolas Pontikos: Queen Mary University of London
Jun Wang: Queen Mary University of London
Hemanth Tummala: Queen Mary University of London
Ahad Fahad H. Al Seraihi: Queen Mary University of London
Jenna Alnajar: Queen Mary University of London
Findlay Bewicke-Copley: Queen Mary University of London
Hannah Armes: Queen Mary University of London
Michael Barnett: University of British Columbia
Adrian Bloor: Christie Hospital
Csaba Bödör: Semmelweis University
David Bowen: St James’s University Hospital
Pierre Fenaux: Hôpital St Louis/Université Paris
Andrew Green: Our Lady’s Children’s Hospital
Andrew Hallahan: Queensland Children’s Hospital
Henrik Hjorth-Hansen: St Olavs Hospital and Institute of Cancer Research and Molecular Medicine (IKM) Norwegian University of Science and Technology (NTNU)
Upal Hossain: Barts NHS Trust
Sally Killick: The Royal Bournemouth Hospital NHS Foundation Trust
Sarah Lawson: Birmingham Children’s Hospital
Mark Layton: Hammersmith Hospital
Alison M. Male: Great Ormond Street Hospital
Judith Marsh: King’s College Hospital
Priyanka Mehta: University Hospitals Bristol NHS Foundation Trust
Rogier Mous: Huispostnummer
Josep F. Nomdedéu: Universitat Autònoma de Barcelona
Carolyn Owen: Foothills Medical Centre
Jiri Pavlu: Hammersmith Hospital
Elspeth M. Payne: University College London
Rachel E. Protheroe: University Hospitals Bristol NHS Foundation Trust
Claude Preudhomme: Centre Hospitalier Regional Universitaire de Lille
Nuria Pujol-Moix: Universitat Autònoma de Barcelona
Aline Renneville: Broad Institute of Harvard and MIT
Nigel Russell: Nottingham University Hospitals NHS Trust
Anand Saggar: St George’s Hospital Medical School
Gabriela Sciuccati: Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”
David Taussig: Royal Marsden Hospital
Cynthia L. Toze: University of British Columbia
Anne Uyttebroeck: University Hospitals Leuven
Peter Vandenberghe: University Hospitals Leuven
Brigitte Schlegelberger: Medizinische Hochschule Hannover
Tim Ripperger: Medizinische Hochschule Hannover
Doris Steinemann: Medizinische Hochschule Hannover
John Wu: British Columbia Children’s Hospital
Joanne Mason: Birmingham Women’s NHS Foundation Trust
Paula Page: Birmingham Women’s NHS Foundation Trust
Susanna Akiki: Hamad Bin Khalifa Medical City (HBKM)
Kim Reay: Birmingham Women’s NHS Foundation Trust
Jamie D. Cavenagh: Barts NHS Trust
Vincent Plagnol: University College London
Javier F. Caceres: University of Edinburgh
Jude Fitzgibbon: Queen Mary University of London
Inderjeet Dokal: Queen Mary University of London

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14829-5

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