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Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

Nature genetics, 2015-07, Vol.47 (7), p.717-726 [Peer Reviewed Journal]

COPYRIGHT 2015 Nature Publishing Group ;COPYRIGHT 2015 Nature Publishing Group ;Copyright Nature Publishing Group Jul 2015 ;ISSN: 1061-4036 ;EISSN: 1546-1718 ;DOI: 10.1038/ng.3304 ;PMID: 25985138

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Title:
Factors influencing success of clinical genome sequencing across a broad spectrum of disorders
Author: Taylor, Jenny C ; Martin, Hilary C ; Lise, Stefano ; Broxholme, John ; Cazier, Jean-Baptiste ; Rimmer, Andy ; Kanapin, Alexander ; Fiddy, Simon ; Allan, Chris ; Aricescu, A Radu ; Babbs, Christian ; Becq, Jennifer ; Beeson, David ; Bignell, Patricia ; Buckle, Veronica J ; Bull, Katherine ; Cais, Ondrej ; Cario, Holger ; Chapel, Helen ; Copley, Richard R ; Cornall, Richard ; Craft, Jude ; Dahan, Karin ; Davenport, Emma E ; Dendrou, Calliope ; Devuyst, Olivier ; Fenwick, Aimée L ; Flint, Jonathan ; Gilbert, Rodney D ; Goriely, Anne ; Green, Angie ; Greger, Ingo H ; Grocock, Russell ; Gruszczyk, Anja V ; Hastings, Robert ; Hatton, Edouard ; Higgs, Doug ; Hill, Adrian ; Holmes, Chris ; Howard, Malcolm ; Hughes, Linda ; Humburg, Peter ; Johnson, David ; Kingsbury, Zoya ; Kini, Usha ; Knight, Julian C ; Krohn, Jonathan ; Lamble, Sarah ; Langman, Craig ; Lonie, Lorne ; Luck, Joshua ; McCarthy, Davis ; McGowan, Simon J ; McMullin, Mary Frances ; Miller, Kerry A ; Murray, Lisa ; Németh, Andrea H ; Nesbit, M Andrew ; Nutt, David ; Ormondroyd, Elizabeth ; Oturai, Annette Bang ; Pagnamenta, Alistair ; Patel, Smita Y ; Percy, Melanie ; Petousi, Nayia ; Piazza, Paolo ; Polanco-Echeverry, Guadalupe ; Popitsch, Niko ; Powrie, Fiona ; Pugh, Chris ; Quek, Lynn ; Robbins, Peter A ; Robson, Kathryn ; Russo, Alexandra ; Sahgal, Natasha ; van Schouwenburg, Pauline A ; Schuh, Anna ; Silverman, Earl ; Simmons, Alison ; Sørensen, Per Soelberg ; Sweeney, Elizabeth ; Taylor, John ; Thakker, Rajesh V ; Tomlinson, Ian ; Trebes, Amy ; Twigg, Stephen Rf ; Vyse, Tim ; Wall, Steven A ; Watkins, Hugh ; Whyte, Michael P ; Witty, Lorna ; Wright, Ben ; Yau, Chris ; Humphray, Sean ; Ratcliffe, Peter J ; Bell, John I ; Wilkie, Andrew Om ; Bentley, David ; Donnelly, Peter ; McVean, Gilean
Subjects: Agreements ; Annotations ; Base Sequence ; Data processing ; Disease transmission ; DNA Mutational Analysis ; DNA sequencing ; Families & family life ; Genetic aspects ; Genetic counseling ; Genetic Diseases, Inborn - diagnosis ; Genetic Diseases, Inborn - genetics ; Genetic disorders ; Genetic variation ; Genome, Human ; Genomes ; Grants ; Health aspects ; High-Throughput Nucleotide Sequencing ; Humans ; Identification and classification ; Methods ; Molecular Diagnostic Techniques ; Molecular Sequence Annotation ; Mutation ; Nucleotide sequencing ; Polymorphism, Single Nucleotide ; Sensitivity and Specificity ; Software ; Studies ; Success
Is Part Of: Nature genetics, 2015-07, Vol.47 (7), p.717-726
Description: 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.
Publisher: United States: Nature Publishing Group
Language: English
Identifier: ISSN: 1061-4036
EISSN: 1546-1718
DOI: 10.1038/ng.3304
PMID: 25985138
Source: Geneva Foundation Free Medical Journals at publisher websites
AUTh Library subscriptions: ProQuest Central
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Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

COPYRIGHT 2015 Nature Publishing Group ;COPYRIGHT 2015 Nature Publishing Group ;Copyright Nature Publishing Group Jul 2015 ;ISSN: 1061-4036 ;EISSN: 1546-1718 ;DOI: 10.1038/ng.3304 ;PMID: 25985138

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