Phen2Gene: rapid phenotype-driven gene prioritization for rare diseases

Area of Science:

• Genomics and Bioinformatics
• Medical Genetics
• Computational Biology

Background:

• Human Phenotype Ontology (HPO) terms are crucial for characterizing patient phenotypes in diagnostics.
• Existing HPO annotations and gene databases facilitate but can be enhanced for rare disease genetic diagnosis.
• Accurate gene prioritization is essential for diagnosing rare and undiagnosed diseases.

Purpose of the Study:

• To develop a novel HPO-driven gene prioritization tool, Phen2Gene, for improved rare disease genetic diagnosis.
• To integrate HPO annotations, gene-disease, and gene-gene databases into a probabilistic model.
• To provide a fast and accurate phenotype-driven tool for clinical diagnosis.

Main Methods:

• Developed Phen2Gene, a tool utilizing a probabilistic model and the HPO2Gene Knowledgebase (H2GKB).
• H2GKB integrates HPO annotations, gene-disease, and gene-gene databases.
• Phen2Gene processes HPO terms or PhenoPacket descriptions to generate prioritized gene lists and gene-disease relationships.

Main Results:

• Phen2Gene demonstrates superior speed and accuracy compared to existing gene prioritization tools.
• The tool accurately outputs gene-disease relationships, aiding in clinical diagnosis.
• Benchmarking data includes 197 patients from 76 articles and 85 de-identified patient HPO terms.

Conclusions:

• Phen2Gene serves as a real-time, phenotype-driven gene prioritization tool for rare undiagnosed diseases.
• The tool is available as a command-line application, web server, and web service.
• Phen2Gene significantly aids clinicians in the genetic diagnosis of rare diseases.