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Jezkova, J.* ; McClatchey, M.A.* ; Shaw, S.* ; Vaughan, R.* ; Halstead, J.* ; Egner, I.* ; Whatley, S.D.* ; Kamath, A.* ; Murch, O.* ; Varghese, V.* ; Irving, R.* ; Gardner, J.F.* ; Ahmed, A.* ; Tully, I.* ; Jain, V.* ; Rogers, M.T.* ; Sansbury, F.H.* ; Clarke, A.J.* ; Pottinger, C.* ; Rodriguez, M.V.* ; Naudé, J.t.W.* ; Bettridge, A.* ; Martin-Geary, A.C.* ; Wagner, N.* ; Gagneur, J. ; Votruba, M.* ; Bunyan, D.J.* ; Ashelford, K.* ; Giles, P.J.* ; Williams, H.J.* ; Morgan, S.* ; Sampson, J.R.* ; Fry, A.E.*

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

Eur. J. Hum. Genet., DOI: 10.1038/s41431-026-02234-3 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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 type Article: Journal article
Document type Scientific Article
Keywords Genomics ; Personal Genomics ; Genome ; Exome Sequencing ; Medical Genetics ; Dna Sequencing ; Exome ; Proband ; 1000 Genomes Project; Variants; Mutations; Spectrum
ISSN (print) / ISBN 1018-4813
e-ISSN 1476-5438
Journal European Journal of Human Genetics
Publisher Springer
Publishing Place The Campus, 4 Crinan St, London, N1 9xw, England
Reviewing status Peer reviewed
Institute(s) Institute of Computational Biology (ICB)
Grants RCUK | Medical Research Council (MRC)
Deutsche Forschungsgemeinschaft (German Research Foundation)