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2020.03.23.20041467V1.Full.Pdf medRxiv preprint doi: https://doi.org/10.1101/2020.03.23.20041467; this version posted March 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome Matthew C Sims*1,2,3, Louisa Mayer*1,2, Janine H Collins*1,2,4, Tadbir K Bariana*1,4,5, Karyn Megy1,2,6, Cecile Lavenu-Bombled7, Denis Seyres1,2,6, Laxmikanth Kollipara8, Frances S Burden1,2,6, Daniel Greene1,6,9, Dave Lee10, Antonio Rodriguez-Romera1,2, Marie-Christine Alessi11, William J Astle2,9, Wadie F Bahou12, Loredana Bury13, Elizabeth Chalmers14, Rachael Da Silva10, Erica De Candia15,16, Sri V V Deevi1,6, Samantha Farrow1,2,6, Keith Gomez5, Luigi Grassi1,2,6, Andreas Greinacher17, Paolo Gresele13, Dan Hart18, Marie-Françoise Hurtaud7, Anne M Kelly1, Ron Kerr19, Sandra Le Quellec20, Thierry Leblanc7, Eva B Leinøe21, Rutendo Mapeta1,6, Harriet McKin- ney1,2,6, Alan D Michelson22, Sara Morais23,24, Diane Nugent25, Sofia Papadia1,2,6, Soo J Park26, John Pasi18, Gian Marco Podda27, Man-Chiu Poon28, Rachel Reed10, Mallika Sekhar29, Hanna Shalev30, Suthesh Sivapalaratnam1,4, Orna Steinberg-Shemer31,32, Jonathan C Stephens1,6, Robert C Tait33, Ernest Turro1,2,6,9, John K M Wu34, Barbara Zieger35, NIHR BioResource6, Taco W Kuijpers36,37, Anthony D Whetton10, Albert Sickmann8,38,39, Kathleen Freson40, Kate Downes1,6, Wendy N Erber41,42, Mattia Frontini1,2,43, Paquita Nurden44, Willem H Ouwehand1,2,6,45, Remi Favier**7,46, and Jose A Guerrero**1,2 1 Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK; 2 National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK; NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 1 medRxiv preprint doi: https://doi.org/10.1101/2020.03.23.20041467; this version posted March 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . 3 Oxford Haemophilia and Thrombosis Centre, Oxford University Hospitals NHS Foundation Trust, NIHR Oxford Biomedical Research Centre, Oxford, UK; 4 Department of Haematology, Barts Health NHS Trust, London, UK; 5 Royal Free London, NHS Foundation Trust, London, UK; 6 NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Cam- pus, Cambridge, UK; 7 Assistance Publique-Hôpitaux de Paris, Centre de Reference des Pathologies Plaquettaires, Hôpitaux Armand Trousseau, Bicêtre, Robert Debré, Paris, France; 8 Leibniz-Institut für Analytische Wissenschaften - ISAS - e. V., Dortmund, Germany; 9 Medical Research Council Biostatistics Unit, Forvie Site, Robinson Way, Cambridge Biomedical Campus, Cambridge, UK; 10 Stoller Biomarker Discovery Centre, Division of Cancer Sciences, School of Med- ical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; 11 Centre for CardioVascular and Nutrition Research, INSERM 1263, INRAE 1260, Marseille, France; 12 Stony Brook University School of Medicine, Stony Brook, USA; 13 Department of Medicine, Section of Internal and Cardiovascular Medicine, Uni- versity of Perugia, Perugia, Italy; 2 medRxiv preprint doi: https://doi.org/10.1101/2020.03.23.20041467; this version posted March 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . 14 Royal Hospital for Sick Children, Glasgow, UK; 15 Institute of Internal Medicine and Geriatrics, Catholic University School of Medi- cine, Rome, Italy; 16 Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; 17 Institut für Immunologie und Transfusionsmedizin, Universitätsmedizin Greif- swald, Greifswald, Germany; 18 The Royal London Hospital Haemophilia Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 19 Department of Haematology, Ninewells Hospital and Medical School, Dundee, UK; 20 Service d'hématologie biologique, Hospices Civils de Lyon, Lyon, France; 21 Department of Haematology, Rigshospitalet, Copenhagen, Denmark; 22 Center for Platelet Research Studies, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA; 23 Serviço de Hematologia Clínica, Hospital de Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal; 24 Unidade Multidisciplinar de Investigação Biomédica, Instituto de Ciências Bio- médicas, Universidade do Porto, Porto, Portugal; 25 Center for Inherited Bleeding Disorders, Children's Hospital of Orange County, Or- ange, CA, USA; 3 medRxiv preprint doi: https://doi.org/10.1101/2020.03.23.20041467; this version posted March 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . 26 University of California San Diego, La Jolla, CA, USA; 27 Unità di Medicina 2, ASST Santi Paolo e Carlo, Dipartimento di Scienze della Sa- lute, Università degli Studi di Milano, Milan, Italy; 28 University of Calgary Cumming School of Medicine and Southern Alberta Rare Blood and Bleeding Disorders Comprehensive Care Program, Calgary, AB, Canada; 29 Department of Haematology, Royal Free London NHS Trust, London, UK; 30 Department of Pediatric Hematology/Oncology, Soroka Medical Center, Faculty of Medicine, Ben-Gurion University, Beer Sheva, Israel; 31 Department of Hematology-Oncology, Schneider Children's Medical Center of Is- rael, Petach Tikva, Israel; 32 Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; 33 Department of Haematology, Royal Infirmary, Glasgow, UK; 34 Division of Hematology-Oncology, University of British Columbia and BC Chil- dren's Hospital, Vancouver, BC, Canada; 35 Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hemato- logy and Oncology, Medical Center - Faculty of Medicine, University of Freiburg, Freiburg, Germany; 36 Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam University Medical Center, Amsterdam, The Netherlands; 4 medRxiv preprint doi: https://doi.org/10.1101/2020.03.23.20041467; this version posted March 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . 37 Sanquin Research Institute, Department of Blood Cell Research, University of Am- sterdam, Amsterdam, The Netherlands; 38 Department of Chemistry, College of Physical Sciences, University of Aberdeen, Aberdeen, UK; 39 Medizinische Fakultät, Medizinisches Proteom Center, Ruhr-Universität Bochum, Bochum, Germany; 40 University of Leuven, Department of Cardiovascular Sciences, Center for Molecu- lar and Vascular Biology, Leuven, Belgium; 41 Faculty of Health and Medical Sciences, The University of Western Australia, Crawley, Australia; 42 PathWest Laboratory Medicine, The University of Western Australia, Nedlands, Australia; 43 British Heart Foundation, Cambridge Centre for Research Excellence, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK; 44 Institut Hospitalo-Universitaire LIRYC, PTIB, Hôpital Xavier Arnozan, Pessac, France; 45 Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK; 46 INSERM UMR 1170, Gustave Roussy Cancer Campus, Universite Paris-Saclay, Villejuif, France 5 medRxiv preprint doi: https://doi.org/10.1101/2020.03.23.20041467; this version posted March 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . * Authors contributed equally to this work ** Authors contributed equally to this work Corresponding authors: Janine H Collins and Jose A Guerrero Department of Haematology NHS Blood and Transplant Building University of Cambridge Cambridge Biomedical Campus Cambridge CB2 0PT UK Email: [email protected]; [email protected] Tel: +441223588095 Abstract Gray platelet syndrome (GPS) is a rare recessive disorder caused by variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet ɑ-granules, splenomegaly and bone marrow (BM) fibrosis. Due to its rarity, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To dis- cern the spectrum of pathological features, we performed a detailed clinical genotypic and phenotypic study of 47 GPS patients. We identified 33 new causal variants in NBEAL2. Our GPS patient cohort exhibited known phenotypes, including macro- thrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splen- omegaly, and elevated serum vitamin B12 levels. We also observed novel clinical 6 medRxiv preprint
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