A novel phenotype-guided genome analysis pipeline for variant discovery

Area of Science:

• Genomics
• Ophthalmology
• Medical Genetics

Background:

• Inherited retinal dystrophies (IRDs) are a diverse group of vision disorders with over 360 identified genes.
• A significant percentage of IRD cases remain undiagnosed after standard genetic testing, necessitating advanced sequencing methods.

Purpose of the Study:

• To develop and validate ReDGAP (Retinal Degeneration Genome Analysis Pipeline), a phenotype-guided genome analysis tool for diagnosing IRDs.
• To improve the diagnostic yield of genetic testing for patients with unresolved IRD cases.

Main Methods:

• ReDGAP integrates clinical phenotyping with variant scoring for prioritizing genetic variants.
• The pipeline supports joint analysis of multiple variant classes using an evidence-weighted scoring system.
• In silico predictors and functional validation were employed to assess variant impact.

Main Results:

• ReDGAP achieved a 100% re-identification rate in previously solved IRD cases.
• The pipeline diagnosed 80% of previously unsolved IRD cases, identifying various variant types including intronic, duplication, and deletion mutations.
• Functional studies confirmed transcript disruptions and regulatory impacts for identified variants.

Conclusions:

• ReDGAP enhances the diagnosis of inherited retinal dystrophies by integrating phenotypic data with comprehensive variant analysis.
• This approach facilitates timely molecular diagnoses and identifies patients eligible for gene-targeted therapies.
• ReDGAP represents a clinically relevant model for rare disease investigation in precision health.