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

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.

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Publication Details

Journal
European Journal of Human Genetics
Published
2026-09-28
DOI
https://doi.org/10.1038/s41431-026-02234-3
Primary Topic
Genomics and Rare Diseases
Type
article
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Reanalysis of genomic data doubles the diagnostic yield for Welsh patients recruited to the UK 100,000 Genomes Project

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

Julien Gagneur, Arveen Kamath, Hywel J. Williams, Marcela Votruba, Vani Jain, Nils Wagner, Martin A. McClatchey, Andrew E. Fry, Jennifer F. Gardner, Oliver Murch, Julian R. Sampson, David J. Bunyan, Sharon D. Whatley, Jana Jezkova, Iris Egner, Kevin Ashelford, Siân Morgan, Rachel Irving, Angus John Clarke, Joseph Halstead, Rhys Vaughan, Peter J. Giles, Sophie Shaw, Francis H. Sansbury, Alexandra C Martin-Geary, Ayesha Ahmed, Mark T. Rogers, Caroline Pottinger, Maribel Verdesoto Rodriguez, Johann te Water Naudé, Aimee Bettridge, Ian Tully, Vinod Varghese
article en

Abstract

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.

European Journal of Human Genetics
Centre for Human Genetics (GB), Salisbury District Hospital (GB), University Hospital of Wales (GB), Helmholtz Zentrum München (DE), University of Oxford (GB), Institut für Humangenetik (DE), Technical University of Munich (DE), Cardiff University (GB)
Partnerships for the goals
Openalex Percentile: Top 12%
Genomics and Rare Diseases
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