Human phenotype ontology annotation and cluster analysis to unravel genetic defects in 707 cases with unexplained bleeding and platelet disordersReportar como inadecuado

Human phenotype ontology annotation and cluster analysis to unravel genetic defects in 707 cases with unexplained bleeding and platelet disorders - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Genome Medicine

, 7:36

First Online: 09 April 2015Received: 24 November 2014Accepted: 05 March 2015


BackgroundHeritable 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.

MethodsWe 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.

ResultsWe 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.

ConclusionsThese 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.

AbbreviationsBPDbleeding and platelet disorders

HGMDHuman Genome Mutation Database

HPOHuman Phenotype Ontology

HPSHermansky-Pudlak syndrome

HTShigh throughput sequencing

ICinformation content

ICDInternational Classification of Diseases

LPVlikely pathogenic variant

LTAlight transmission aggregometry

MPVmean platelet volume

MYH9-RDMYH9-related disorder

OMIMOnline Mendelian Inheritance in Man

PAMPartitioning Around Medoids


PVpathogenic variant

SNOMED-CTSystematized Nomenclature of Medicine Clinical Terminology

VUSvariant of unknown significance

WASWiskott-Aldrich syndrome

Sarah K Westbury, Ernest Turro, Daniel Greene, Claire Lentaigne, Anne M Kelly, Tadbir K Bariana, Willem H Ouwehand, Sylvia Richardson, Andrew D Mumford and Kathleen Freson contributed equally to this work.

Electronic supplementary materialThe online version of this article doi:10.1186-s13073-015-0151-5 contains supplementary material, which is available to authorized users.

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Autor: Sarah K Westbury - Ernest Turro - Daniel Greene - Claire Lentaigne - Anne M Kelly - Tadbir K Bariana - Ilenia Simeoni -


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