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

Adaptor Proteins, Signal Transducing / genetics Adenosine Deaminase / genetics Axonemal Dyneins / genetics Cohort Studies Germ-Line Mutation Humans Leukemia, Myeloid, Acute / genetics Myelodysplastic Syndromes / genetics Nonsense Mediated mRNA Decay Pedigree Perforin / genetics Platelet Membrane Glycoproteins / genetics RNA Helicases / genetics Receptors, Interleukin-17 / genetics Vesicular Transport Proteins / genetics Exome Sequencing

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
25 02 2020
Historique:
received: 04 02 2019
accepted: 27 01 2020
entrez: 27 2 2020
pubmed: 27 2 2020
medline: 23 5 2020
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-020-14829-5 PMID: 32098966 PMC: PMC7042299
pubmed: 32098966
doi: 10.1038/s41467-020-14829-5
pii: 10.1038/s41467-020-14829-5
pmc: PMC7042299
doi:

Substances chimiques

Adaptor Proteins, Signal Transducing 0
IL17RA protein, human 0
PRF1 protein, human 0
Platelet Membrane Glycoproteins 0
Receptors, Interleukin-17 0
SEC23B protein, human 0
SH2B3 protein, human 0
Vesicular Transport Proteins 0
platelet membrane glycoprotein VI 0
Perforin 126465-35-8
DHX34 protein, human EC 2.7.7.-
ADA protein, human EC 3.5.4.4
Adenosine Deaminase EC 3.5.4.4
RNA Helicases EC 3.6.4.13
Axonemal Dyneins EC 3.6.4.2
DNAH9 protein, human EC 3.6.4.2

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1044

Subventions

Organisme : Medical Research Council
ID : MC_UU_00007/7
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M018830/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P018440/1
Pays : United Kingdom

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Auteurs

Ana Rio-Machin (A)

Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK. a.rio-machin@qmul.ac.uk.
ORCID: 0000-0001-6733-9752

Tom Vulliamy (T)

Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, UK. t.vulliamy@qmul.ac.uk.

Nele Hug (N)

MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

Amanda Walne (A)

Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, UK.

Kiran Tawana (K)

Department of Haematology, Addenbrooke's Hospital, Cambridge, UK.

Shirleny Cardoso (S)

Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, UK.

Alicia Ellison (A)

Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, UK.
ORCID: 0000-0002-8490-8512

Nikolas Pontikos (N)

Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, UK.

Jun Wang (J)

Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
ORCID: 0000-0003-2509-9599

Hemanth Tummala (H)

Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, UK.

Ahad Fahad H Al Seraihi (AFH)

Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.

Jenna Alnajar (J)

Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, UK.

Findlay Bewicke-Copley (F)

Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
ORCID: 0000-0003-1292-7965

Hannah Armes (H)

Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.

Michael Barnett (M)

The Leukemia/BMT Program of British Columbia, Division of Hematology, Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.

Adrian Bloor (A)

Department of Haematology, Christie Hospital, Manchester, UK.

Csaba Bödör (C)

MTA-SE Lendulet Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
ORCID: 0000-0002-0729-692X

David Bowen (D)

Department of Haematology, St James's University Hospital, Leeds, UK.

Pierre Fenaux (P)

Service d'hématologie Séniors, Hôpital St Louis/Université Paris, Paris, France.

Andrew Green (A)

National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.

Andrew Hallahan (A)

Children's Health Queensland Hospital and Health Service, Queensland Children's Hospital, South Brisbane, QLD, Australia.

Henrik Hjorth-Hansen (H)

Department of Hematology, St Olavs Hospital and Institute of Cancer Research and Molecular Medicine (IKM) Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
ORCID: 0000-0002-2670-5696

Upal Hossain (U)

Department of Haematology, Whipps Cross Hospital, Barts NHS Trust, London, UK.

Sally Killick (S)

Department of Haematology, The Royal Bournemouth Hospital NHS Foundation Trust, Bournemouth, UK.

Sarah Lawson (S)

Department of Haematology, Birmingham Children's Hospital, Birmingham, UK.

Mark Layton (M)

Centre for Haematology, Imperial College London, Hammersmith Hospital, London, UK.

Alison M Male (AM)

Clinic Genetics Unit, Great Ormond Street Hospital, London, UK.

Judith Marsh (J)

Department of Haematological Medicine, Haematology Institute, King's College Hospital, London, UK.

Priyanka Mehta (P)

Bristol Haematology Unit, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.

Rogier Mous (R)

UMC Utrecht Cancer Center, Universitair Medisch Centrum Utrecht, Huispostnummer, Utrecht, Netherlands.

Josep F Nomdedéu (JF)

Laboratori d´Hematologia, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
ORCID: 0000-0003-3399-346X

Carolyn Owen (C)

Division of Hematology and Hematological Malignancies, Foothills Medical Centre, Calgary, AB, Canada.

Jiri Pavlu (J)

Centre for Haematology, Imperial College London, Hammersmith Hospital, London, UK.
ORCID: 0000-0001-5219-5637

Elspeth M Payne (EM)

Department of Haematology, UCL Cancer Institute, University College London, London, UK.
ORCID: 0000-0001-5841-778X

Rachel E Protheroe (RE)

Bristol Haematology Unit, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.

Claude Preudhomme (C)

Laboratory of Hematology, Biology and Pathology Center, Centre Hospitalier Regional Universitaire de Lille, Lille, France.
Jean-Pierre Aubert Research Center, INSERM, Universitaire de Lille, Lille, France.

Nuria Pujol-Moix (N)

Laboratori d´Hematologia, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

Aline Renneville (A)

Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Nigel Russell (N)

Centre for Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK.

Anand Saggar (A)

Clinical Genetics, St George's Hospital Medical School, London, UK.

Gabriela Sciuccati (G)

Servicio de Hematologia y Oncologia, Hospital de Pediatría "Prof. Dr. Juan P. Garrahan", Ciudad Autonoma de Buenos Aires, Argentina.

David Taussig (D)

Haemato-oncology Department, Royal Marsden Hospital, Sutton, UK.

Cynthia L Toze (CL)

The Leukemia/BMT Program of British Columbia, Division of Hematology, Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.

Anne Uyttebroeck (A)

Department of Hematology, University Hospitals Leuven, Leuven, Belgium.
ORCID: 0000-0001-5644-424X

Peter Vandenberghe (P)

Department of Hematology, University Hospitals Leuven, Leuven, Belgium.
ORCID: 0000-0003-4719-1935

Brigitte Schlegelberger (B)

Institut für Humangenetik, Medizinische Hochschule Hannover, Hannover, Germany.

Tim Ripperger (T)

Institut für Humangenetik, Medizinische Hochschule Hannover, Hannover, Germany.

Doris Steinemann (D)

Institut für Humangenetik, Medizinische Hochschule Hannover, Hannover, Germany.
ORCID: 0000-0001-8797-0816

John Wu (J)

British Columbia Children's Hospital, Vancouver, BC, Canada.

Joanne Mason (J)

West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Birmingham, UK.

Paula Page (P)

West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Birmingham, UK.

Susanna Akiki (S)

Department of Laboratory Medicine & Pathology, Qatar Rehabilitation Institute, Hamad Bin Khalifa Medical City (HBKM), Doha, Qatar.

Kim Reay (K)

West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Birmingham, UK.

Jamie D Cavenagh (JD)

Department of Haematology, St Bartholomew's Hospital, Barts NHS Trust, London, UK.

Vincent Plagnol (V)

Genetics Institute, University College London, London, UK.
ORCID: 0000-0002-5597-9215

Javier F Caceres (JF)

MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
ORCID: 0000-0001-8025-6169

Jude Fitzgibbon (J)

Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK. j.fitzgibbon@qmul.ac.uk.

Inderjeet Dokal (I)

Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, UK. i.dokal@qmul.ac.uk.
Barts Health NHS Trust, London, UK. i.dokal@qmul.ac.uk.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › The complex genetic landscape of familial MDS...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Aminohydrolases › Nucleoside deaminases › Adenosine deaminase › The complex genetic landscape of familial MDS...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Acid anhydride hydrolases › Adenosine triphosphatases › Moteurs moléculaires › Dynéines de l'axonème › The complex genetic landscape of familial MDS...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › The complex genetic landscape of familial MDS...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation germinale › The complex genetic landscape of familial MDS...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The complex genetic landscape of familial MDS...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Leucémies › Leucémie myéloïde › Leucémie aigüe myéloïde › The complex genetic landscape of familial MDS...
questionsmedicales.fr › Hémopathies et maladies lymphatiques › Hémopathies › Maladies de la moelle osseuse › Syndromes myélodysplasiques › The complex genetic landscape of familial MDS...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Maturation post-transcriptionnelle des ARN › Dégradation des ARNm non-sens › The complex genetic landscape of familial MDS...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Pedigree › The complex genetic landscape of familial MDS...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Perforines › Perforine › The complex genetic landscape of familial MDS...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs immunologiques › Glycoprotéines de membrane plaquettaire › The complex genetic landscape of familial MDS...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Phosphotransferases › Nucleotidyltransferases › RNA nucleotidyltransferases › RNA helicases › The complex genetic landscape of familial MDS...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs immunologiques › Récepteurs aux cytokines › Récepteurs aux interleukines › Récepteurs à l'interleukine-17 › The complex genetic landscape of familial MDS...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines du transport vésiculaire › The complex genetic landscape of familial MDS...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ADN › Séquençage du génome entier › Séquençage de l'exome › The complex genetic landscape of familial MDS...