A Novel Approach to Interrogating Whole Genome Sequencing Data to Optimise Clinical Utility

Area of Science:

• Genomic Medicine
• Rare Disease Diagnostics
• Bioinformatics

Background:

• The 100,000 Genomes Project aimed to utilize whole genome sequencing (WGS) for rare disease diagnosis.
• Evaluating the performance of genomic analytics in a specific cohort is crucial for clinical implementation.

Purpose of the Study:

• To assess the diagnostic yield of genomic analytics in the Northern Ireland 100,000 Genomes Project cohort.
• To evaluate the effectiveness of a two-pronged approach including first-line analysis and reanalysis of inconclusive cases.

Main Methods:

• Whole genome sequencing (WGS) data processing followed national protocols by Genomics England (GEL).
• A novel internal method employed GEL virtual panels for initial prioritization and Exomiser for reanalysis of undiagnosed cases.
• Retrospective collection of genomic records was used for service evaluation.

Main Results:

• A 20.2% diagnostic yield (89/440 patients) was achieved.
• The secondary reanalysis pathway identified 30.3% of diagnoses missed by initial interpretation.
• The secondary approach showed higher effectiveness in prioritizing pathogenic variants (89.9% vs 69.7%).

Conclusions:

• Pre-classification variant selection and reanalysis are vital for improving clinical WGS quality.
• Initial panel-based variant selection can expedite interpretation but may miss diagnoses.
• Revisiting undiagnosed cases yielded an additional ~6% diagnostic rate, highlighting the need for multi-disciplinary approaches.