title: Human phenotype ontology annotation and cluster analysis to unravel genetic defects in 707 cases with unexplained bleeding and platelet disorders.
abstract: BACKGROUND
  Heritable bleeding and platelet disorders (BPD) are heterogeneous and frequently have an unknown genetic basis. The BRIDGE-BPD study aims to discover new causal genes for BPD by high throughput sequencing using cluster analyses based on improved and standardised deep, multi-system phenotyping of cases.
  
  
  METHODS
  We report a new approach in which the clinical and laboratory characteristics of BPD cases are annotated with adapted Human Phenotype Ontology (HPO) terms. Cluster analyses are then used to characterise groups of cases with similar HPO terms and variants in the same genes.
  
  
  RESULTS
  We show that 60% of index cases with heritable BPD enrolled at 10 European or US centres were annotated with HPO terms indicating abnormalities in organ systems other than blood or blood-forming tissues, particularly the nervous system. Cases within pedigrees clustered closely together on the bases of their HPO-coded phenotypes, as did cases sharing several clinically suspected syndromic disorders. Cases subsequently found to harbour variants in ACTN1 also clustered closely, even though diagnosis of this recently described disorder was not possible using only the clinical and laboratory data available to the enrolling clinician.
  
  
  CONCLUSIONS
  These findings validate our novel HPO-based phenotype clustering methodology for known BPD, thus providing a new discovery tool for BPD of unknown genetic basis. This approach will also be relevant for other rare diseases with significant genetic heterogeneity.
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Westbury
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK ; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK ; Medical Research Council Biostatistics Unit, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Ernest
authors.initials: E
authors.lastname: Turro
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK ; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK ; Medical Research Council Biostatistics Unit, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Greene
authors.affiliation: Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London, UK ; Imperial College Healthcare NHS Trust, DuCane Road, London, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Lentaigne
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK ; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Kelly
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, UK ; The Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London, UK.
authors.forename: Tadbir K
authors.initials: TK
authors.lastname: Bariana
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK ; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Simeoni
authors.affiliation: Institut Hospitalo-Universitaire LIRYC, PTIB, Hôpital Xavier Arnozan, Pessac, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Pillois
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK ; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Antony
authors.initials: A
authors.lastname: Attwood
authors.affiliation: Department of Haematology, Guys and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Austin
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK ; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Sjoert Bg
authors.initials: SB
authors.lastname: Jansen
authors.affiliation: Institut für Immunologie und Transfusionsmedizin Universitätsmedizin Ernst-Moritz-Arndt Universität, Greifswald, Germany.
authors.forename: Tamam
authors.initials: T
authors.lastname: Bakchoul
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK ; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Abi
authors.initials: A
authors.lastname: Crisp-Hihn
authors.affiliation: Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA Australia.
authors.forename: Wendy N
authors.initials: WN
authors.lastname: Erber
authors.affiliation: Haematological Laboratory, Trousseau Children's Hospital and INsermU1009, Paris, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Favier
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK ; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Foad
authors.affiliation: Department of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Gattens
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK ; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Jolley
authors.affiliation: Department of Haematology, Great Ormond Street Hospital for Children NHS Trust, London, UK.
authors.forename: Ri
authors.initials: R
authors.lastname: Liesner
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK ; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Meacham
authors.affiliation: Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London, UK ; Imperial College Healthcare NHS Trust, DuCane Road, London, UK.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Millar
authors.affiliation: Institut Hospitalo-Universitaire LIRYC, PTIB, Hôpital Xavier Arnozan, Pessac, France.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Nurden
authors.affiliation: 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, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Perry
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK ; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Pawan
authors.initials: P
authors.lastname: Poudel
authors.affiliation: Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, USA.
authors.forename: Sol
authors.initials: S
authors.lastname: Schulman
authors.affiliation: Lehrstuhl für Experimentelle Biomedizin, Universitätsklinikum Würzburg, Würzburg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Schulze
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK ; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Stephens
authors.affiliation: Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Furie
authors.affiliation: Institut für Medizinische Genetik und Humangenetik, Charité Universitätsmedizin, Berlin, Germany ; Max Planck Institute for Molecular Genetics, Berlin, Germany ; Institute for Bioinformatics, Department of Mathematics and Computer Science Freie Universität, Berlin, Germany.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Robinson
authors.affiliation: Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
authors.forename: Chris
authors.initials: C
authors.lastname: van Geet
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK ; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK ; Medical Research Council Biostatistics Unit, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Augusto
authors.initials: A
authors.lastname: Rendon
authors.affiliation: The Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London, UK.
authors.forename: Keith
authors.initials: K
authors.lastname: Gomez
authors.affiliation: Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Laffan
authors.affiliation: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, USA ; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA.
authors.forename: Michele P
authors.initials: MP
authors.lastname: Lambert
authors.affiliation: Institut Hospitalo-Universitaire LIRYC, PTIB, Hôpital Xavier Arnozan, Pessac, France.
authors.forename: Paquita
authors.initials: P
authors.lastname: Nurden
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK ; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.affiliation: Medical Research Council Biostatistics Unit, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Richardson
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Mumford
authors.affiliation: Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Freson