Reanalysis of genomic data doubles the diagnostic yield for Welsh patients recruited to the UK 100,000 Genomes Project

Jezkova, Jana, McClatchey, Martin A., Shaw, Sophie, Vaughan, Rhys, Halstead, Joseph, Clarke, Angus ORCID: https://orcid.org/0000-0002-1200-9286, Giles, Peter ORCID: https://orcid.org/0000-0003-3143-6854, Votruba, Marcela ORCID: https://orcid.org/0000-0002-7680-9135, Williams, Hywel J. ORCID: https://orcid.org/0000-0001-7758-0312, Sampson, Julian ORCID: https://orcid.org/0000-0002-2902-2348 and Fry, Andrew ORCID: https://orcid.org/0000-0001-9778-6924 2026. Reanalysis of genomic data doubles the diagnostic yield for Welsh patients recruited to the UK 100,000 Genomes Project. European Journal of Human Genetics 10.1038/s41431-026-02234-3

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Abstract

The 100,000 Genomes Project (100KGP) undertook genome sequencing of patients with rare diseases and cancer to study the role that genes play in disease, and to integrate genomics into UK healthcare. To contribute to 100KGP, the Wales Genomic Medicine Centre (a partnership between the NHS All Wales Medical Genomics Service (AWMGS), Cardiff University and Genomics England) recruited 438 individuals from 154 families that had been subject to pre-genomic genetic testing without reaching a diagnosis. The majority of probands (64%, 98/154) had neurological or neurodevelopmental phenotypes. Genome sequencing, variant calling, gene-based filtering and variant prioritisation were performed by Genomics England. AWMGS undertook clinical interpretation, validation and reporting of variants. Initial diagnostic yield was 20.8% (32/154) with variants of uncertain significance (VUS) reported for 11 more families. Most of the initial findings (83.7%, 36/43) could have been detected by clinical exome sequencing which was standard of care in Wales at the time. Reanalysis of the 100KGP Wales data using updated variant prioritisation tools, expanded gene lists, re-phenotyping and segregation studies, has increased diagnostic yield to 42.2% (65/154) (an improvement of 103%). RNA analysis was used to clarify the clinical significance of VUS in COQ4, ENPP1, GATAD2B, NCAPD2, and THOC2. These findings demonstrate the clinical utility of genome sequencing, RNA analysis, and periodic reanalysis of genomic data.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Optometry and Vision Sciences Schools > Medicine
Additional Information:	Full list of authors available: https://doi.org/10.1038/s41431-026-02234-3
Publisher:	Springer Nature [academic journals on nature.com]
ISSN:	1018-4813
Date of First Compliant Deposit:	2 October 2026
Date of Acceptance:	3 September 2026
Last Modified:	02 Oct 2026 15:45
URI:	https://orca.cardiff.ac.uk/id/eprint/189965

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