Improved diagnosis of rare disease patients through application of constrained coding region annotation and de novo status

Odhams, Chris and Williams, Hywel J. ORCID: https://orcid.org/0000-0001-7758-0312 2025. Improved diagnosis of rare disease patients through application of constrained coding region annotation and de novo status. Genetics in Medicine 27 (7) , 101447. 10.1016/j.gim.2025.101447 Item availability restricted.

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	Elsevier
ISSN:	1098-3600
Date of First Compliant Deposit:	21 May 2025
Date of Acceptance:	15 April 2025
Last Modified:	28 May 2025 14:30
URI:	https://orca.cardiff.ac.uk/id/eprint/178401

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