title: Rare variants in GP1BB are responsible for autosomal dominant macrothrombocytopenia.
abstract: The von Willebrand receptor complex, which is composed of the glycoproteins Ibα, Ibβ, GPV, and GPIX, plays an essential role in the earliest steps in hemostasis. During the last 4 decades, it has become apparent that loss of function of any 1 of 3 of the genes encoding these glycoproteins (namely, GP1BA, GP1BB, and GP9) leads to autosomal recessive macrothrombocytopenia complicated by bleeding. A small number of variants in GP1BA have been reported to cause a milder and dominant form of macrothrombocytopenia, but only 2 tentative reports exist of such a variant in GP1BB By analyzing data from a collection of more than 1000 genome-sequenced patients with a rare bleeding and/or platelet disorder, we have identified a significant association between rare monoallelic variants in GP1BB and macrothrombocytopenia. To strengthen our findings, we sought further cases in 2 additional collections in the United Kingdom and Japan. Across 18 families exhibiting phenotypes consistent with autosomal dominant inheritance of macrothrombocytopenia, we report on 27 affected cases carrying 1 of 9 rare variants in GP1BB.
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge, United Kingdom.|Department of Haematology, Barts Health National Health Service Trust, London, United Kingdom.
authors.forename: Suthesh
authors.initials: S
authors.lastname: Sivapalaratnam
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Sarah K
authors.identifier: 0000-0002-0950-8148
authors.initials: SK
authors.lastname: Westbury
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge, United Kingdom.|National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Stephens
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge, United Kingdom.|Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Greene
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge, United Kingdom.|National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom.
authors.forename: Kate
authors.initials: K
authors.lastname: Downes
authors.affiliation: Department of Haematology, Great Ormond Street Hospital for Children National Health Service Trust, London, United Kingdom.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Kelly
authors.affiliation: Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London, United Kingdom.|Imperial College Healthcare National Health Service Trust, London, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Lentaigne
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge, United Kingdom.|Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge, United Kingdom.
authors.forename: William J
authors.initials: WJ
authors.lastname: Astle
authors.affiliation: Crystal and Structural Chemistry, Department of Chemistry, Faculty of Science, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Huizinga
authors.affiliation: Institut Hospitalo-Universitaire LIRYC, Hôpital Xavier Arnozan, Pessac, France.
authors.forename: Paquita
authors.initials: P
authors.lastname: Nurden
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge, United Kingdom.
authors.forename: Sofia
authors.initials: S
authors.lastname: Papadia
authors.affiliation: Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
authors.forename: Kathelijne
authors.initials: K
authors.lastname: Peerlinck
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Penkett
authors.affiliation: Department of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Perry
authors.affiliation: Kent Haemophilia Thrombosis Centre at East Kent Hospitals University NHS Foundation Trust, Canterbury, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: Roughley
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge, United Kingdom.|National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Simeoni
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge, United Kingdom.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Stirrups
authors.affiliation: Department of Haematology, Barts Health National Health Service Trust, London, United Kingdom.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Hart
authors.affiliation: Department of Haematology, Royal Infirmary, Glasgow, United Kingdom.
authors.forename: R Campbell
authors.initials: RC
authors.lastname: Tait
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.|School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Mumford
authors.affiliation: Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London, United Kingdom.|Imperial College Healthcare National Health Service Trust, London, United Kingdom.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Laffan
authors.affiliation: Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Freson
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge, United Kingdom.|National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom.|Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom; and.
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.affiliation: Department of Advanced Diagnosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kunishima
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge, United Kingdom.|National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom.|Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge, United Kingdom.
authors.forename: Ernest
authors.identifier: 0000-0002-1820-6563
authors.initials: E
authors.lastname: Turro
mesh_terms: D000483:Alleles; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D015870:Gene Expression; D005799:Genes, Dominant; D015894:Genome, Human; D006470:Hemorrhage / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010976:Platelet Count; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000235:genetics*; D013921:Thrombocytopenia / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D019038:Platelet Glycoprotein GPIb-IX Complex; C094990:adhesion receptor