1. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders
- Author
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Lynn Quek, Anne Goriely, Ondrej Cais, Christopher Yau, Lars Fugger, John Broxholme, Niko Popitsch, David Beeson, Zoya Kingsbury, M. Andrew Nesbit, David J. Nutt, Christopher Holmes, Andrew J. Rimmer, Fredrik Karpe, John Taylor, Andrea H. Németh, Veronica J. Buckle, Rodney D. Gilbert, Natasha Sahgal, Sian E. Piret, Alistair T. Pagnamenta, Elizabeth Sweeney, Stefano Lise, Sarah Lamble, Moustafa Attar, Christian Babbs, Mary Frances McMullin, Adrian V. S. Hill, Ingo H. Greger, Per Soelberg Sørensen, Michael P. Whyte, Paolo Piazza, Lorna Witty, Lorne Lonie, Emma E. Davenport, Peter J. Ratcliffe, Peter Humburg, Simon J. McGowan, Holger Cario, Chris Allan, Usha Kini, Malcolm F. Howard, Alexandra Russo, Simon Fiddy, Fiona Powrie, Pauline A. van Schouwenburg, Jude Craft, Andrew O.M. Wilkie, Aimee L. Fenwick, Jennifer Becq, Elizabeth Ormondroyd, Nayia Petousi, Richard R. Copley, Joshua Luck, David Buck, Hilary C. Martin, Katherine R. Bull, Holm H. Uhlig, Russell J. Grocock, Timothy J. Vyse, Smita Y. Patel, Gerton Lunter, Sean Humphray, Helen Chapel, Peter Donnelly, Karin Dahan, Calliope A. Dendrou, Edward Blair, Peter A. Robbins, Davis J. McCarthy, Kerry A. Miller, Rajesh V. Thakker, A. Radu Aricescu, Gilean McVean, Alison Simmons, Annette Bang Oturai, Julian C. Knight, David W. Johnson, Craig B. Langman, Earl D. Silverman, Anja V. Gruszczyk, Olivier Devuyst, Jean-Baptiste Cazier, Paresh Vyas, John I. Bell, Kathryn J. H. Robson, Ian Tomlinson, Jenny C. Taylor, Amy Trebes, Anna Schuh, Linda Hughes, Stephen R.F. Twigg, Hugh Watkins, Celeste Bento, Melanie J. Percy, Robert W. Hastings, Jonathan Flint, Richard J. Cornall, Edouard Hatton, Doug Higgs, P Bignell, Guadalupe Polanco-Echeverry, Angie Green, Jon P. Krohn, Ben Wright, David Bentley, Christopher W. Pugh, Steven A. Wall, Lisa Murray, and Alexander Kanapin
- Subjects
HEREDITARY BREAST ,Candidate gene ,medicine.medical_specialty ,DNA Mutational Analysis ,EXOME ,LONG-QT SYNDROME ,Biology ,Genome ,Polymorphism, Single Nucleotide ,Sensitivity and Specificity ,DNA sequencing ,Article ,OVARIAN-CANCER ,CANDIDATE GENES ,Genetics ,medicine ,BREAST-CANCER ,Humans ,JUVENILE MYELOMONOCYTIC LEUKEMIA ,Exome ,Whole genome sequencing ,Genetics & Heredity ,SEVERE INTELLECTUAL DISABILITY ,Science & Technology ,Base Sequence ,Genome, Human ,Genetic Diseases, Inborn ,High-Throughput Nucleotide Sequencing ,Molecular Sequence Annotation ,GERMLINE MUTATIONS ,11 Medical And Health Sciences ,06 Biological Sciences ,Molecular Diagnostic Techniques ,Medical genetics ,Human genome ,Biological plausibility ,DISEASE GENE-DISCOVERY ,Life Sciences & Biomedicine ,Developmental Biology - Abstract
To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.
- Published
- 2016
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