Phen2Gene: rapid phenotype-driven gene prioritization for rare diseases

Abstract

Human Phenotype Ontology (HPO) terms are increasingly used in diagnostic settings to aid in the characterization of patient phenotypes. The HPO annotation database is updated frequently and can provide detailed phenotype knowledge on various human diseases, and many HPO terms are now mapped to candidate causal genes with binary relationships. To further improve the genetic diagnosis of rare diseases, we incorporated these HPO annotations, gene–disease databases and gene–gene databases in a probabilistic model to build a novel HPO-driven gene prioritization tool, Phen2Gene. Phen2Gene accesses a database built upon this information called the HPO2Gene Knowledgebase (H2GKB), which provides weighted and ranked gene lists for every HPO term. Phen2Gene is then able to access the H2GKB for patient-specific lists of HPO terms or PhenoPacket descriptions supported by GA4GH (http://phenopackets.org/), calculate a prioritized gene list based on a probabilistic model and output gene–disease relationships with great accuracy. Phen2Gene outperforms existing gene prioritization tools in speed and acts as a real-time phenotype-driven gene prioritization tool to aid the clinical diagnosis of rare undiagnosed diseases. In addition to a command line tool released under the MIT license (https://github.com/WGLab/Phen2Gene), we also developed a web server and web service (https://phen2gene.wglab.org/) for running the tool via web interface or RESTful API queries. Finally, we have curated a large amount of benchmarking data for phenotype-to-gene tools involving 197 patients across 76 scientific articles and 85 patients’ de-identified HPO term data from the Children’s Hospital of Philadelphia.

The History of Gene Hunting in Hereditary Spinocerebellar Degeneration: Lessons From the Past and Future Perspectives

“…The comprehensiveness of WES and WGS should not lead us to underestimate the role of proper clinical phenotyping in diagnosing genetic diseases ( Pena et al, 2018 ). Tools that incorporate phenotypic data in NGS analysis pipelines are under development and have been used with success ( Thuriot et al, 2018 ; Zhao et al, 2020 ). These include tools that empower the clinicians to have a central role in prioritizing variants, e.g., tools that apply gene-pertinence metrics ( Segal et al, 2020 ).…”

Multiplex gene and phenotype network to characterize shared genetic pathways of epilepsy and autism

“…The phenotype network was generated based on a phenotypic similarity score between pairs of genes representing how similar they are in their phenotype associations. For each of the 1707 epilepsy- and autism-associated genes, all phenotype associations were retrieved from the Phen2Gene knowledgebase, a comprehensive and standardized database of phenotype-gene associations that standardizes phenotypes using the Human Phenotype Ontology (HPO) 30 , 31 . Only HPO IDs under the parent “Phenotypic abnormality” (HP:0000118) were used in order to retrieve the most relevant phenotypic information.…”

“…Therefore, in this present study, our aim is to characterize genetic modules and prioritize candidate genes for both disorders, taking advantage of the large number of expert-compiled and well-established disease-associated genes for each of the diseases. First, we constructed a phenotype network of epilepsy- and autism-associated genes using gene-phenotype associations from the comprehensive database of Phen2Gene, a phenotype-drive gene prioritization tool 30 . We then integrated the protein–protein interaction (PPI) relationships of these genes using a multilayer network.…”

PhenCards: a data resource linking human phenotype information to biomedical knowledge

“…Pharos [ 30 ] information for UniProt [ 40 ] disease aliases is expandable in PhenCards to obtain Gene Ontology [ 41 ] data, expression data, pathway data, and drug development stage data for the term. For further facilitating genetic studies, PhenCards utilizes Phen2Gene [ 38 ] and Pharos again to obtain relevant gene information for extracted HPO terms for user queries, and these genes link out to MedlinePlus [ 42 ] and the Pharos site. The Pharos drug target data can be further explored in PhenCards to learn ligands for the target, protein-protein interactions, its expression in certain tissues, and its novelty.…”