Screening 100,000 newborns using whole genome sequencing: the generation study

David Bick; Meekai To; Amanda Pichini; Lindsay Ratan; Christine Cavanagh; Ciara Leckie; Harriet Etheredge; Mathilde Leblond; Liz Gardner; Dalia Kasperaviciute; Joanna Ziff; Alice Tuff-Lacey; Ellen Thomas; Richard Scott

doi:10.1530/endoabs.111.ES1.1

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Endocrine Abstracts (2025) 111 ES1.1 | DOI: 10.1530/endoabs.111.ES1.1

BSPED2025 Symposia Endocrine Symposium 1 (3 abstracts)

Screening 100,000 newborns using whole genome sequencing: the generation study

David Bick , Meekai To , Amanda Pichini , Lindsay Ratan , Christine Cavanagh , Ciara Leckie , Harriet Etheredge , Mathilde Leblond , Liz Gardner , Dalia Kasperaviciute , Joanna Ziff , Alice Tuff-Lacey , Ellen Thomas & Richard Scott

Author affiliations

Genomics England, London, United Kingdom

Worldwide, research programs are examining the clinical utility of whole genome sequencing (WGS) as an adjunct to current newborn screening for treatable genetic disorders (https://www.iconseq.org/). Genomics England in partnership with National Health Service England (NHSE) have undertaken a Research Ethics Committee approved research study, the Generation Study (GS), to understand the utility of WGS to diagnose rare but treatable conditions by sequencing 100,000 unselected newborns. Genes and their associated conditions for 922 gene-condition pairs (GCPs) were assessed against 4 principles (https://www.genomicsengland.co.uk/initiatives/newborns). GCPs fulfilling the principles were reviewed by paediatric specialists and NHSE. Women were recruited during pregnancy at sites across England. Cord blood was the source of DNA for the study. When cord blood was missed, a heel prick was taken. Core laboratories performed DNA extraction then sequencing using the NovaSeq 6000 Sequencing System. WGS data was analysed with a Genomics England purpose-built pipeline. To maximize positive predictive value, only pathogenic and likely pathogenic variants were prioritized. Variants prioritised by the pipeline were reviewed by a laboratory clinical scientist. ‘Condition suspected’ results were passed to a specialist with experience treating the condition to decide whether to contact parents. The specialist seeing the child arranged confirmatory tests and treatment as appropriate. The ‘condition suspected’ cases were confirmed with non-molecular confirmatory tests, which exists for nearly all selected conditions. 488 gene-condition pairs, found in 462 genes resulting in 208 conditions are included in the programme. There are 37 recruitment sites accepting participants. 18,349 families have enrolled. 12,286 newborn genomes have been sequenced and analysed. 460 cases have been prioritized by the pipeline for clinical scientist review. 46 cases representing 33 different disorders were returned to a specialist for review and decision whether to report to parents. Evaluation of the GS will includes assessing the process and acceptability of newborn sequencing as well as clinical utility and an economic analysis. The Genomics England GS will provide critical experience and extensive evaluation to help define the risks and benefits of genomics as an adjunct to newborn screening in a national program.