Improved diagnosis of patients with rare diseases through the application of constrained coding region annotation and de novo status.

Chris Odhams; Hywel J Williams

doi:10.1016/j.gim.2025.101447

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Improved diagnosis of patients with rare diseases through the application of constrained coding region annotation and de novo status.

Chris Odhams·Hywel J Williams

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Abstract

PURPOSE: Identifying the pathogenic variant in a patient with rare disease (RD) is the first step in ending their diagnostic odyssey. De novo (Dn) variants affecting protein-coding DNA are a well-established cause of Mendelian disorders in patients with RD. Constrained coding regions (CCRs) are specific segments of coding DNA that are devoid of functional variants in healthy individuals. METHODS: We evaluated the diagnostic utility of incorporating combined Dn/CCR status into the variant prioritization cascade for patients with RD that have undergone genomic sequencing. Using the Genomics England 100,000 Genomes Project v12, we selected 3090 trios that have undergone diagnostic evaluation and been analyzed with an advanced Dn identification pipeline. RESULTS: Our analysis shows that the diagnostic rate increased from 71% in the full cohort to 87% for Dn/CCR variants. Of note, manual evaluation of the Dn/CCR variants from undiagnosed patients with clinical follow-up revealed a diagnosis for 13 further patients. This outcome increases the diagnostic rate for Dn/CCR variants to 91% and suggests that the application of this metric can prioritize diagnostic variants in undiagnosed patients. CONCLUSION: We demonstrate the potential clinical utility of performing bespoke Dn analyses of patients with RD and for incorporating CCR information into the filtering cascade to prioritize pathogenic variants.

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Humans Rare Diseases Open Reading Frames Molecular Sequence Annotation Genomics Genome, Human 100,000 Genomes Project Constrained coding regions De novo Diagnosis Rare disease Journal Article Research Support, Non-U.S. Gov't

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Chris Odhams, Hywel J Williams. 2025-04-21. Improved diagnosis of patients with rare diseases through the application of constrained coding region annotation and de novo status.. https://doi.org/10.1016/j.gim.2025.101447

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