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Genome Med. 2015 Apr 9;7(1):36. doi: 10.1186/s13073-015-0151-5. eCollection 2015.

Human phenotype ontology annotation and cluster analysis to unravel genetic defects in 707 cases with unexplained bleeding and platelet disorders.

Author information

1
School of Clinical Sciences, University of Bristol, Bristol, UK.
2
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.
3
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.
4
Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK ; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK.
5
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.
6
Institut Hospitalo-Universitaire LIRYC, PTIB, Hôpital Xavier Arnozan, Pessac, France.
7
Department of Haematology, Guys and St Thomas' NHS Foundation Trust, London, UK.
8
Institut für Immunologie und Transfusionsmedizin Universitätsmedizin Ernst-Moritz-Arndt Universität, Greifswald, Germany.
9
Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA Australia.
10
Haematological Laboratory, Trousseau Children's Hospital and INsermU1009, Paris, France.
11
Department of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
12
Department of Haematology, Great Ormond Street Hospital for Children NHS Trust, London, UK.
13
Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
14
Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, USA.
15
Lehrstuhl für Experimentelle Biomedizin, Universitätsklinikum Würzburg, Würzburg, Germany.
16
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.
17
The Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London, UK.
18
Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London, UK.
19
Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, USA ; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA.
20
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.
21
Medical Research Council Biostatistics Unit, Cambridge Biomedical Campus, Cambridge, UK.
22
School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.

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.

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