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

Abstract

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

Inherited platelet disorders: toward DNA-based diagnosis

“…104 HPO coding is used by the Deciphering of Developmental Disorders 105 and 100 000 Genomes Projects, and thus far, 1247 probands with BPDs have been HPO coded. 2 This revealed the presence of nonhematological pathologies in 60% of cases, particularly in the central nervous (eg, autism spectrum disorder), skeletal (eg, osteoporosis), and immune systems. 2 This insight into the more complex spectrum of pathologies in IPD cases is important for the provision of care, which often warrants a multidisciplinary approach.…”

“…2 This revealed the presence of nonhematological pathologies in 60% of cases, particularly in the central nervous (eg, autism spectrum disorder), skeletal (eg, osteoporosis), and immune systems. 2 This insight into the more complex spectrum of pathologies in IPD cases is important for the provision of care, which often warrants a multidisciplinary approach. Additionally, standardized phenotyping by means of HPO terms is critical for IPD gene discovery across large collections of cases.…”

“…16 In addition, whole exome sequencing (WES) was also instrumental in discovering variants in GFI1B responsible for a GPS-like syndrome 14 60 The results of the rare diseases pilot phase of the 100 000 Genomes Project 83 indicate that a large number of IPD genes remain to be discovered. Genome sequencing results of the DNA samples of hundreds of probands with uncharacterized BPDs, analyzed using assigned human phenotype ontology (HPO) terms, 2 have helped identify pathogenic variants in known IPD genes in almost 20% of cases. New algorithms to compare cases with similar phenotypes 48,84 have been used to identify 2 novel IPD genes (DIAPH1 and SRC) 22,48 and several putative ones.…”

A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders

“…The aims of the ThromboGenomics project are to develop a multigene HTS platform for the diagnosis of BPDs, to deposit knowledge about novel pathogenic variants in a sustainable and freely available database, and to leverage systematic Human Phenotype Ontology (HPO)-term based coding of patient phenotypes 4 to improve our understanding of genotype-phenotype correlations in BPDs. To deliver the project to high scientific and ethical standards, a global ThromboGenomics network of clinicians and researchers with expertise in BPDs (see supplemental Figure 1, available on the Blood Web site) was formed.…”

“…Previously, we have defined a BPD case as a patient having an abnormal platelet count, volume, morphology, or function, or with a tendency to bleed abnormally. 4 The abnormal phenotypes must furthermore be judged to have a genetic basis, thereby ruling out diseases that may have been acquired or thought to be caused by exposure to known environmental risk factors. For the purposes of this study, we also include patients with an abnormal tendency to thrombus formation in our definition.…”