GeneTerpret: a customizable multilayer approach to genomic variant prioritization and interpretation

Area of Science:

• Genomics
• Bioinformatics
• Medical Genetics

Background:

• Variant interpretation is a major challenge in medical genomics.
• Current methods involve manual searching across numerous databases and tools.
• This process is time-consuming and can be inefficient.

Purpose of the Study:

• To develop a platform, GeneTerpret, to streamline the genomic variant interpretation process.
• To improve the ease, speed, and accuracy of identifying potentially causal variants.
• To provide a quantitative approach to gene validity and variant pathogenicity.

Main Methods:

• Developed the GeneTerpret platform to collate data from existing tools and databases.
• Implemented a phenotype-driven query system for variant categorization.
• Assigned quantitative validity scores to genes using genotype-phenotype data, homology, interactions, expression, and animal models.
• Utilized American College of Medical Genetics and Genomics (ACMG) criteria for variant pathogenicity tiers.

Main Results:

• GeneTerpret demonstrated high concordance with expert-curated databases: 97.2% with ClinGen and 83.5% with DECIPHER.
• Similar concordance was observed when compared to internal expert-interpreted clinical datasets.
• The platform provides a prioritized list of potentially causal variants/genes.

Conclusions:

• GeneTerpret offers a flexible, user-friendly platform to accelerate genomic interpretation.
• The system's modularity allows customization for specific analytical needs.
• GeneTerpret enhances the accuracy and efficiency of identifying disease-causing variants.