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Delivering effective genome sequencing in pediatric care: From research in the 100,000 Genomes Project to routine clinical practice.

Emma Wakeling·Rashida Baptiste·Clarissa Rocca·Bethan Hoskins·Christopher Clarkson·Lyn S Chitty·Arianna Tucci
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Abstract

PURPOSE: Genome sequencing (GS) is increasingly used to investigate rare conditions, primarily in children. The 100,000 Genomes Project (100KG) evaluated GS ahead of implementation in the English National Health Service. In 2020, the National Health Service Genomic Medicine Service (GMS) became the first public health care system to offer GS in routine clinical care. We investigate how learning from 100KG informed GMS service delivery. METHODS: We compare GS outcomes in children tested at a large pediatric hospital via GMS (n = 501) and 100KG research (n = 1759). RESULTS: GMS diagnostic yield (29%) was higher than that in 100KG (22%) (P < .0016). Median age at testing was 8 years in 100KG and 6 in the GMS (P < .05). In 100KG, the diagnostic yield was <10% for 15 indications, none of which are included in GMS testing. 100KG data showed little benefit to application of >3 panels. Use of fewer but larger GMS panels resulted in a significantly higher number of genes tested per patient: median 2801 vs 1373 in 100KG (P < .001). In 100KG, diagnostic yield was not significantly increased by testing more than 3 family members (n = 34/142, 24%). CONCLUSION: Learning from 100KG has informed GS clinical service delivery, resulting in higher diagnostic yields and earlier age at testing. Lessons are broadly applicable to all services providing GS, enabling earlier access to tailored management with fewer investigations.

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HumansChildGenetic TestingGenomicsWhole Genome SequencingFemalePediatricsMaleGenome, HumanChild, PreschoolAdolescentInfantDelivery of Health CareClinical practiceDiagnostic yieldGenome sequencingPediatricResearchJournal ArticleResearch Support, Non-U.S. Gov't

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Emma Wakeling, Rashida Baptiste, Clarissa Rocca, Bethan Hoskins, Christopher Clarkson, Lyn S Chitty, Arianna Tucci. 2025-12-02. Delivering effective genome sequencing in pediatric care: From research in the 100,000 Genomes Project to routine clinical practice.. https://doi.org/10.1016/j.gim.2025.101619

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