Dataset Information

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

ABSTRACT: 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.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.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.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.

SUBMITTER: Westbury SK

PROVIDER: S-EPMC4422517 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Westbury Sarah K SK Turro Ernest E Greene Daniel D Lentaigne Claire C Kelly Anne M AM Bariana Tadbir K TK Simeoni Ilenia I Pillois Xavier X Attwood Antony A Austin Steve S Jansen Sjoert Bg SB Bakchoul Tamam T Crisp-Hihn Abi A Erber Wendy N WN Favier Rémi R Foad Nicola N Gattens Michael M Jolley Jennifer D JD Liesner Ri R Meacham Stuart S Millar Carolyn M CM Nurden Alan T AT Peerlinck Kathelijne K Perry David J DJ Poudel Pawan P Schulman Sol S Schulze Harald H Stephens Jonathan C JC Furie Bruce B Robinson Peter N PN van Geet Chris C Rendon Augusto A Gomez Keith K Laffan Michael A MA Lambert Michele P MP Nurden Paquita P Ouwehand Willem H WH Richardson Sylvia S Mumford Andrew D AD Freson Kathleen K

Genome medicine 20150409 1

<h4>Background</h4>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.<h4>Methods</h4>We report a new approach in which the clinical and laboratory characteristics of BPD cases are annotated with adapted Human Phenotype Ontology (HPO) terms. Cluste ...[more]

PMID: 25949529

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Project description:The Gene Ontology Annotation (GOA) database (http://www.ebi.ac.uk/GOA) aims to provide high-quality electronic and manual annotations to the UniProt Knowledgebase (Swiss-Prot, TrEMBL and PIR-PSD) using the standardized vocabulary of the Gene Ontology (GO). As a supplementary archive of GO annotation, GOA promotes a high level of integration of the knowledge represented in UniProt with other databases. This is achieved by converting UniProt annotation into a recognized computational format. GOA provides annotated entries for nearly 60,000 species (GOA-SPTr) and is the largest and most comprehensive open-source contributor of annotations to the GO Consortium annotation effort. By integrating GO annotations from other model organism groups, GOA consolidates specialized knowledge and expertise to ensure the data remain a key reference for up-to-date biological information. Furthermore, the GOA database fully endorses the Human Proteomics Initiative by prioritizing the annotation of proteins likely to benefit human health and disease. In addition to a non-redundant set of annotations to the human proteome (GOA-Human) and monthly releases of its GO annotation for all species (GOA-SPTr), a series of GO mapping files and specific cross-references in other databases are also regularly distributed. GOA can be queried through a simple user-friendly web interface or downloaded in a parsable format via the EBI and GO FTP websites. The GOA data set can be used to enhance the annotation of particular model organism or gene expression data sets, although increasingly it has been used to evaluate GO predictions generated from text mining or protein interaction experiments. In 2004, the GOA team will build on its success and will continue to supplement the functional annotation of UniProt and work towards enhancing the ability of scientists to access all available biological information. Researchers wishing to query or contribute to the GOA project are encouraged to email: goa@ebi.ac.uk.

Dataset Information

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

Publications

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

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