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PMID: 25985138 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Nature genetics ·Vol. 47 ·No. 7 ·2015-07-00 ·Pages 717-726

Taylor JC, Martin HC, Lise S, Broxholme J, Cazier JB, Rimmer A, Kanapin A, Lunter G, Fiddy S, Allan C, Aricescu AR, Attar M, Babbs C, Becq J, Beeson D, Bento C, Bignell P, Blair E, Buckle VJ, Bull K, Cais O, Cario H, Chapel H, Copley RR, Cornall R, Craft J, Dahan K, Davenport EE, Dendrou C, Devuyst O, Fenwick AL, Flint J, Fugger L, Gilbert RD, Goriely A, Green A, Greger IH, Grocock R, Gruszczyk AV, Hastings R, Hatton E, Higgs D, Hill A, Holmes C, Howard M, Hughes L, Humburg P, Johnson D, Karpe F, Kingsbury Z, Kini U, Knight JC, Krohn J, Lamble S, Langman C, Lonie L, Luck J, McCarthy D, McGowan SJ, McMullin MF, Miller KA, Murray L, Németh AH, Nesbit MA, Nutt D, Ormondroyd E, Oturai AB, Pagnamenta A, Patel SY, Percy M, Petousi N, Piazza P, Piret SE, Polanco-Echeverry G, Popitsch N, Powrie F, Pugh C, Quek L, Robbins PA, Robson K, Russo A, Sahgal N, van Schouwenburg PA, Schuh A, Silverman E, Simmons A, Sørensen PS, Sweeney E, Taylor J, Thakker RV, Tomlinson I, Trebes A, Twigg SR, Uhlig HH, Vyas P, Vyse T, Wall SA, Watkins H, Whyte MP, Witty L, Wright B, Yau C, Buck D, Humphray S, Ratcliffe PJ, Bell JI, Wilkie AO, Bentley D, Donnelly P, McVean G

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.

MeSH Terms
Base Sequence DNA Mutational Analysis Genetic Diseases, Inborn/diagnosis,genetics Genome, Human High-Throughput Nucleotide Sequencing Humans Molecular Diagnostic Techniques Molecular Sequence Annotation Polymorphism, Single Nucleotide Sensitivity and Specificity
Authors & Affiliations
110 authors, click to expand affiliations / ORCID
Taylor Jenny C
NIHR Comprehensive Biomedical Research Centre, Oxford, UK. | Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Martin Hilary C
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Lise Stefano
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Broxholme John
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Cazier Jean-Baptiste
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Rimmer Andy
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Kanapin Alexander
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Lunter Gerton
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Fiddy Simon
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Allan Chris
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Aricescu A Radu
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Attar Moustafa
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Babbs Christian
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Becq Jennifer
Illumina Cambridge Limited, Saffron Walden, UK.
Beeson David
Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Bento Celeste
Hematology Department, Centro Hospitalar e Universitário de Coimbra, Portugal.
Bignell Patricia
Molecular Haematology Department, Oxford University Hospitals NHS Trust, Oxford, UK.
Blair Edward
Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.
Buckle Veronica J
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Bull Katherine
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. | Centre for Cellular and Molecular Physiology, University of Oxford, Oxford, UK.
Cais Ondrej
Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, UK.
Cario Holger
Department of Pediatrics and Adolescent Medicine, University Medical Center, Ulm, Germany.
Chapel Helen
Primary Immunodeficiency Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Copley Richard R
NIHR Comprehensive Biomedical Research Centre, Oxford, UK. | Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Cornall Richard
Centre for Cellular and Molecular Physiology, University of Oxford, Oxford, UK.
Craft Jude
NIHR Comprehensive Biomedical Research Centre, Oxford, UK. | Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Dahan Karin
Centre de Génétique Humaine, Institut de Génétique et de Pathologie, Gosselies, Belgium. | Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.
Davenport Emma E
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Dendrou Calliope
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Devuyst Olivier
Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
Fenwick Aimée L
Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Flint Jonathan
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Fugger Lars
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Gilbert Rodney D
University Hospital Southampton NHS Foundation Trust, University of Southampton, Southampton, UK.
Goriely Anne
Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Green Angie
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Greger Ingo H
Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, UK.
Grocock Russell
Illumina Cambridge Limited, Saffron Walden, UK.
Gruszczyk Anja V
Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Hastings Robert
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Hatton Edouard
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Higgs Doug
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Hill Adrian
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. | The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Holmes Chris
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. | Department of Statistics, University of Oxford, Oxford, UK.
Howard Malcolm
NIHR Comprehensive Biomedical Research Centre, Oxford, UK. | Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Hughes Linda
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Humburg Peter
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Johnson David
Craniofacial Unit, Department of Plastic and Reconstructive Surgery, Oxford University Hospitals NHS Trust, Oxford, UK.
Karpe Fredrik
Oxford Laboratory for Integrative Physiology, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.
Kingsbury Zoya
Illumina Cambridge Limited, Saffron Walden, UK.
Kini Usha
Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.
Knight Julian C
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Krohn Jonathan
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Lamble Sarah
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Langman Craig
Kidney Diseases, Feinberg School of Medicine, Northwestern University and the Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
Lonie Lorne
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Luck Joshua
Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
McCarthy Davis
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
McGowan Simon J
Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
McMullin Mary Frances
Centre for Cancer Research and Cell Biology, Queen's University, Belfast, UK.
Miller Kerry A
Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Murray Lisa
Illumina Cambridge Limited, Saffron Walden, UK.
Németh Andrea H
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Nesbit M Andrew
Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.
Nutt David
Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College, London, UK.
Ormondroyd Elizabeth
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Oturai Annette Bang
Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Copenhagen, Denmark.
Pagnamenta Alistair
NIHR Comprehensive Biomedical Research Centre, Oxford, UK. | Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Patel Smita Y
Primary Immunodeficiency Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Percy Melanie
Department of Haematology, Belfast City Hospital, Belfast, UK.
Petousi Nayia
Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Piazza Paolo
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Piret Sian E
Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.
Polanco-Echeverry Guadalupe
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Popitsch Niko
NIHR Comprehensive Biomedical Research Centre, Oxford, UK. | Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Powrie Fiona
Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
Pugh Chris
Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Quek Lynn
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Robbins Peter A
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
Robson Kathryn
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Russo Alexandra
Department of Pediatrics, University Hospital, Mainz, Germany.
Sahgal Natasha
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
van Schouwenburg Pauline A
Primary Immunodeficiency Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Schuh Anna
NIHR Comprehensive Biomedical Research Centre, Oxford, UK. | Department of Oncology, University of Oxford, Oxford, UK.
Silverman Earl
Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Simmons Alison
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. | Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
Sørensen Per Soelberg
Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Copenhagen, Denmark.
Sweeney Elizabeth
Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
Taylor John
NIHR Comprehensive Biomedical Research Centre, Oxford, UK. | Oxford NHS Regional Molecular Genetics Laboratory, Oxford University Hospitals NHS Trust, Oxford, UK.
Thakker Rajesh V
Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.
Tomlinson Ian
NIHR Comprehensive Biomedical Research Centre, Oxford, UK. | Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Trebes Amy
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Twigg Stephen Rf
Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Uhlig Holm H
Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
Vyas Paresh
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Vyse Tim
Division of Genetics, King's College London, Guy's Hospital, London, UK.
Wall Steven A
Craniofacial Unit, Department of Plastic and Reconstructive Surgery, Oxford University Hospitals NHS Trust, Oxford, UK.
Watkins Hugh
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Whyte Michael P
Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St Louis, Missouri, USA.
Witty Lorna
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Wright Ben
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Yau Chris
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Buck David
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Humphray Sean
Illumina Cambridge Limited, Saffron Walden, UK.
Ratcliffe Peter J
Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Bell John I
Office of the Regius Professor of Medicine, University of Oxford, Oxford, UK.
Wilkie Andrew Om
Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Bentley David
Illumina Cambridge Limited, Saffron Walden, UK.
Donnelly Peter
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. | Department of Statistics, University of Oxford, Oxford, UK.
McVean Gilean
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.3304
Published
2015-07-00
Epub
2015-00-18
Pages
717-726
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC4601524
Subset
IM
Grants
Wellcome Trust · 095552 · United Kingdom
Medical Research Council · G0900747 · United Kingdom
Medical Research Council · MC_U137961145 · United Kingdom
Wellcome Trust · 095688 · United Kingdom
Biotechnology and Biological Sciences Research Council · BB/I02593X/1 · United Kingdom
Wellcome Trust · 102731 · United Kingdom
Medical Research Council · MC_UU_12009/11 · United Kingdom
Wellcome Trust · 091182 · United Kingdom
Wellcome Trust · 090532 · United Kingdom
Medical Research Council · MC_U105174197 · United Kingdom
Medical Research Council · G1000801 · United Kingdom
Medical Research Council · MC_UU_12010/3 · United Kingdom
European Research Council · 281824 · International
Department of Health · NIHR-RP-R3-12-026 · United Kingdom
Wellcome Trust · 093329 · United Kingdom
Medical Research Council · MC_UU_12009/1 · United Kingdom
Medical Research Council · MR/M006824/1 · United Kingdom
Medical Research Council · G9825289 · United Kingdom
Medical Research Council · G1000467 · United Kingdom
Medical Research Council · MR/L009609/1 · United Kingdom
Medical Research Council · MC_UU_12010/6 · United Kingdom
Medical Research Council · L009609 · United Kingdom
Wellcome Trust · 100308 · United Kingdom
Wellcome Trust · 102731/Z/13/Z · United Kingdom
British Heart Foundation · RG/12/16/29939 · United Kingdom
Wellcome Trust · 090532/Z/09/Z · United Kingdom
Medical Research Council · MC_UU_12010/7 · United Kingdom
Medical Research Council · MC_UP_1502/3 · United Kingdom
Medical Research Council · MR/L001411/1 · United Kingdom
Medical Research Council · MC_UC_12010/3 · United Kingdom
Medical Research Council · G0900747 91070 · United Kingdom
External Links
PubMed source DOI: 10.1038/ng.3304 PMC Full Text View journal details
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