Genome sequencing with gene panel-based analysis for rare inherited conditions in a publicly funded healthcare system: implications for future testing: implications for future testing

Lynne Hocking, Claire Andrews, Christine Armstrong, Morad Ansari, David Baty, Jonathan Berg, Therese Bradley, Caroline Clark, Austin Diamond, Jill Doherty, Anne Lampe, Ruth McGowan, David J. Moore, Dawn O'Sullivan, Andrew Purvis, Javier Santoyo-Lopez, Paul Westwood, Michael Abbott, Nicola Williams, Scottish Genomes PartnershipTimothy J. Aitman* (Corresponding Author), Zosia Miedzybrodzka* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
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NHS genetics centres in Scotland sought to investigate the Genomics England 100,000 Genomes Project diagnostic utility to evaluate genome sequencing for in rare, inherited conditions. Four regional services recruited 999 individuals from 394 families in 200 rare phenotype categories, with negative historic genetic testing. Genome sequencing was performed at Edinburgh Genomics, and phenotype and sequence data were transferred to Genomics England for variant calling, gene-based filtering and variant prioritisation. NHS Scotland genetics laboratories performed interpretation, validation and reporting. New diagnoses were made in 23% cases – 19% in genes implicated in disease at the time of variant prioritisation, and 4% from later review of additional genes. Diagnostic yield varied considerably between phenotype categories and was minimal in cases with prior exome testing. Genome sequencing with gene panel filtering and reporting achieved improved diagnostic yield over previous historic testing but not over now routine trio-exome sequence tests. Re-interpretation of genomic data with updated gene panels modestly improved diagnostic yield at minimal cost. However, to justify the additional costs of genome vs exome sequencing, efficient methods for analysis of structural variation will be required and / or cost of genome analysis and storage will need to decrease.
Original languageEnglish
Pages (from-to)231-238
Number of pages8
JournalEuropean Journal of Human Genetics
Issue number2
Early online date6 Dec 2022
Publication statusPublished - 1 Feb 2023

Bibliographical note

This study would not be possible without the families, patients, clinicians, nurses, research scientists, laboratory staff, informaticians and the wider Scottish Genomes Partnership team to whom we give grateful thanks. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health). The Scottish Genomes Partnership was funded by the Chief Scientist Office of the Scottish Government Health Directorates (SGP/1) and The Medical Research Council Whole Genome Sequencing for Health and Wealth Initiative (MC/PC/15080). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure.


  • Diagnostic markers
  • genetic testing
  • Health policy


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