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

Author

Listed:
  • 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
    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
    Barts Health NHS Trust)

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.

Suggested Citation

  • 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 & , 2020. "The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14829-5
    DOI: 10.1038/s41467-020-14829-5
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    Cited by:

    1. Hope Mumme & Beena E. Thomas & Swati S. Bhasin & Upaasana Krishnan & Bhakti Dwivedi & Pruthvi Perumalla & Debasree Sarkar & Gulay B. Ulukaya & Himalee S. Sabnis & Sunita I. Park & Deborah DeRyckere & , 2023. "Single-cell analysis reveals altered tumor microenvironments of relapse- and remission-associated pediatric acute myeloid leukemia," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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