1. Evaluating the performance of a clinical genome sequencing program for diagnosis of rare genetic disease, seen through the lens of craniosynostosis
- Author
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Zerin Hyder, Eduardo Calpena, Yang Pei, Rebecca S. Tooze, Helen Brittain, Stephen R.F. Twigg, Deirdre Cilliers, Jenny E.V. Morton, Emma McCann, Astrid Weber, Louise C. Wilson, Andrew G.L. Douglas, Ruth McGowan, Anna Need, Andrew Bond, Ana Lisa Taylor Tavares, Ellen R.A. Thomas, John C. Ambrose, Prabhu Arumugam, Roel Bevers, Marta Bleda, Christopher R. Boustred, Georgia C. Chan, Greg Elgar, Tom Fowler, Adam Giess, Angela Hamblin, Shirley Henderson, Tim J.P. Hubbard, Rob Jackson, Louise J. Jones, Dalia Kasperaviciute, Melis Kayikci, Athanasios Kousathanas, Lea Lahnstein, Sarah E.A. Leigh, Ivonne U.S. Leong, Javier F. Lopez, Fiona Maleady-Crowe, Meriel McEntagart, Federico Minneci, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Peter O’Donovan, Chris A. Odhams, Christine Patch, Mariana Buongermino Pereira, Daniel Perez-Gil, John Pullinger, Tahrima Rahim, Augusto Rendon, Tim Rogers, Kevin Savage, Kushmita Sawant, Afshan Siddiq, Alexander Sieghart, Samuel C. Smith, Alona Sosinsky, Alexander Stuckey, Mélanie Tanguy, Simon R. Thompson, Arianna Tucci, Matthew J. Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M. Wood, Susan L. Hill, Zandra C. Deans, Freya Boardman-Pretty, Mark Caulfield, Richard H. Scott, and Andrew O.M. Wilkie
- Subjects
Proband ,medicine.diagnostic_test ,Base Sequence ,business.industry ,Chromosome Mapping ,Genomics ,Disease ,Bioinformatics ,medicine.disease ,Genome ,DNA sequencing ,Article ,Craniosynostosis ,Craniosynostoses ,Rare Diseases ,medicine ,Humans ,Genetic Testing ,Medical diagnosis ,business ,Genetics (clinical) ,Genetic testing - Abstract
PurposeGenome sequencing (GS) for diagnosis of rare genetic disease is being introduced into the clinic, but the complexity of the data poses challenges for developing pipelines with high diagnostic sensitivity. We evaluated the performance of the Genomics England 100,000 Genomes Project (100kGP) panel-based pipelines, using craniosynostosis as a test disease.MethodsGS data from 114 probands with craniosynostosis and their relatives (314 samples), negative on routine genetic testing, were scrutinized by a specialized research team, and diagnoses compared with those made by 100kGP.ResultsSixteen likely pathogenic/pathogenic variants were identified by 100kGP. Eighteen additional likely pathogenic/pathogenic variants were identified by the research team, indicating that for craniosynostosis, 100kGP panels had a diagnostic sensitivity of only 47%. Measures that could have augmented diagnoses were improved calling of existing panel genes (+18% sensitivity), review of updated panels (+12%), comprehensive analysis of de novo small variants (+29%), and copy-number/structural variants (+9%). Recent NHS England recommendations that partially incorporate these measures should achieve 85% overall sensitivity (+38%).ConclusionGS identified likely pathogenic/pathogenic variants in 29.8% of previously undiagnosed patients with craniosynostosis. This demonstrates the value of research analysis and the importance of continually improving algorithms to maximize the potential of clinical GS.
- Published
- 2021
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