Article | Published:

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

Nature Genetics volume 47, pages 717726 (2015) | Download Citation


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.

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We thank the patients and their families who consented to these studies and the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics for the generation of the sequencing data. Additionally, we are grateful to F. Harrington, C. Mignion, V. Sharma, I. Taylor and I. Westbury for assistance with molecular genetic analysis and the staff of the Oxford University Hospitals Regional Genetics and Immunology Laboratories for the DNA preparation for some of the samples.

This work was funded by a Wellcome Trust Core Award (090532/Z/09/Z) and a Medical Research Council Hub grant (G0900747 91070) to P.D., the NIHR Biomedical Research Centre Oxford, the UK Department of Health's NIHR Biomedical Research Centres funding scheme and Illumina. Additional support is acknowledged from the Biotechnology and Biological Science Research Council (BBSRC) (BB/I02593X/1) to G.L. and G.M.; Wellcome Trust grants 093329, 091182 and 102731 to A.O.M.W. and 100308 to L.F.; the Newlife Foundation for Disabled Children (10-11/04) to A.O.M.W.; AtaxiaUK to A.H.N.; the Haemochromatosis Society to K.R.; European Research Council (FP7/2007-2013) grant agreements 281824 to J.C.K. and 305608 to O.D.; the Jeffrey Modell Foundation NYC and Baxter Healthcare to S.Y.P. and H. Chapel; Action de Recherche Concertée (ARC10/15-029, Communauté Française de Belgique) to O.D.; Fonds de la Recherche Scientifique (FNRS), Fonds de la Recherche Scientifique Médicale (FRSM) and Inter-University Attraction Pole (IUAP; Belgium federal government) to O.D.; the Swiss National Centre of Competence in Research Kidney Control of Homeostasis Program to O.D.; the Gebert Rüf Stiftung (project GRS-038/12) to O.D.; Swiss National Science Foundation grant 310030-146490 to O.D.; the Shriners Hospitals for Children (grant 15958) to M.P.W.; and UK Medical Research Council grants G9825289 and G1000467 to R.V.T., L009609 to A.R.A., G1000801 to D.H. and MC_UC_12010/3 to L.F. The views expressed in this publication are those of the authors and not necessarily those of the UK Department of Health.

Author information

Author notes

    • Jenny C Taylor
    •  & Hilary C Martin

    These authors contributed equally to this work.

    • Peter Donnelly
    •  & Gilean McVean

    These authors jointly supervised this work.


  1. National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Oxford, UK.

    • Jenny C Taylor
    • , Richard R Copley
    • , Jude Craft
    • , Malcolm Howard
    • , Alistair Pagnamenta
    • , Niko Popitsch
    • , Anna Schuh
    • , John Taylor
    •  & Ian Tomlinson
  2. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Jenny C Taylor
    • , Hilary C Martin
    • , Stefano Lise
    • , John Broxholme
    • , Andy Rimmer
    • , Alexander Kanapin
    • , Gerton Lunter
    • , Simon Fiddy
    • , Chris Allan
    • , A Radu Aricescu
    • , Moustafa Attar
    • , Katherine Bull
    • , Richard R Copley
    • , Jude Craft
    • , Emma E Davenport
    • , Jonathan Flint
    • , Angie Green
    • , Edouard Hatton
    • , Adrian Hill
    • , Chris Holmes
    • , Malcolm Howard
    • , Linda Hughes
    • , Peter Humburg
    • , Julian C Knight
    • , Jonathan Krohn
    • , Sarah Lamble
    • , Lorne Lonie
    • , Davis McCarthy
    • , Alistair Pagnamenta
    • , Paolo Piazza
    • , Guadalupe Polanco-Echeverry
    • , Niko Popitsch
    • , Natasha Sahgal
    • , Ian Tomlinson
    • , Amy Trebes
    • , Lorna Witty
    • , Ben Wright
    • , Chris Yau
    • , David Buck
    • , Peter Donnelly
    •  & Gilean McVean
  3. Centre for Computational Biology, University of Birmingham, Edgbaston, UK.

    • Jean-Baptiste Cazier
  4. Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

    • Christian Babbs
    • , Veronica J Buckle
    • , Doug Higgs
    • , Lynn Quek
    • , Kathryn Robson
    •  & Paresh Vyas
  5. Illumina Cambridge, Ltd., Saffron Walden, UK.

    • Jennifer Becq
    • , Russell Grocock
    • , Zoya Kingsbury
    • , Lisa Murray
    • , Sean Humphray
    •  & David Bentley
  6. Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

    • David Beeson
  7. Hematology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

    • Celeste Bento
  8. Molecular Haematology Department, Oxford University Hospitals National Health Service (NHS) Trust, Oxford, UK.

    • Patricia Bignell
  9. Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.

    • Edward Blair
    •  & Usha Kini
  10. Centre for Cellular and Molecular Physiology, University of Oxford, Oxford, UK.

    • Katherine Bull
    •  & Richard Cornall
  11. Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, UK.

    • Ondrej Cais
    •  & Ingo H Greger
  12. Department of Pediatrics and Adolescent Medicine, University Medical Center, Ulm, Germany.

    • Holger Cario
  13. Primary Immunodeficiency Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

    • Helen Chapel
    • , Smita Y Patel
    •  & Pauline A van Schouwenburg
  14. Centre de Génétique Humaine, Institut de Génétique et de Pathologie, Gosselies, Belgium.

    • Karin Dahan
  15. Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.

    • Karin Dahan
  16. MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

    • Calliope Dendrou
    • , Lars Fugger
    •  & Alison Simmons
  17. Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.

    • Olivier Devuyst
  18. Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

    • Aimée L Fenwick
    • , Anne Goriely
    • , Anja V Gruszczyk
    • , Joshua Luck
    • , Simon J McGowan
    • , Kerry A Miller
    • , Stephen R F Twigg
    •  & Andrew O M Wilkie
  19. University Hospital Southampton NHS Foundation Trust, University of Southampton, Southampton, UK.

    • Rodney D Gilbert
  20. Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

    • Robert Hastings
    • , Elizabeth Ormondroyd
    •  & Hugh Watkins
  21. Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

    • Adrian Hill
  22. Department of Statistics, University of Oxford, Oxford, UK.

    • Chris Holmes
    •  & Peter Donnelly
  23. Craniofacial Unit, Department of Plastic and Reconstructive Surgery, Oxford University Hospitals NHS Trust, Oxford, UK.

    • David Johnson
    •  & Steven A Wall
  24. Oxford Laboratory for Integrative Physiology, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.

    • Fredrik Karpe
  25. Kidney Diseases, Feinberg School of Medicine, Northwestern University and the Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.

    • Craig Langman
  26. Centre for Cancer Research and Cell Biology, Queen's University, Belfast, UK.

    • Mary Frances McMullin
  27. Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

    • Andrea H Németh
  28. Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.

    • M Andrew Nesbit
    • , Sian E Piret
    •  & Rajesh V Thakker
  29. Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College, London, UK.

    • David Nutt
  30. Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Copenhagen, Denmark.

    • Annette Bang Oturai
    •  & Per Soelberg Sørensen
  31. Department of Haematology, Belfast City Hospital, Belfast, UK.

    • Melanie Percy
  32. Nuffield Department of Medicine, University of Oxford, Oxford, UK.

    • Nayia Petousi
    • , Chris Pugh
    • , Holm H Uhlig
    •  & Peter J Ratcliffe
  33. Translational Gastroenterology Unit, University of Oxford, Oxford, UK.

    • Fiona Powrie
    •  & Alison Simmons
  34. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.

    • Peter A Robbins
  35. Department of Pediatrics, University Hospital, Mainz, Germany.

    • Alexandra Russo
  36. Department of Oncology, University of Oxford, Oxford, UK.

    • Anna Schuh
  37. Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Earl Silverman
  38. Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK.

    • Elizabeth Sweeney
  39. Oxford NHS Regional Molecular Genetics Laboratory, Oxford University Hospitals NHS Trust, Oxford, UK.

    • John Taylor
  40. Division of Genetics, King's College London, Guy's Hospital, London, UK.

    • Tim Vyse
  41. Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, Missouri, USA.

    • Michael P Whyte
  42. Office of the Regius Professor of Medicine, University of Oxford, Oxford, UK.

    • John I Bell


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P.D. and G.M. jointly supervised and oversaw the WGS500 project. C. Babbs, D. Beeson, P.B., E.B., H. Chapel, R.C., J.F., L.F., D.H., A.H., F.K., U.K., J.C.K., A.H.N., S.Y.P., C.P., F.P., P.J.R., P.A.R., K.R., A. Schuh, A. Simmons, R.V.T., I.T., H.H.U., P.V., H.W. and A.O.M.W. were principal investigators on individual projects. V.J.B., K.B., C.D., O.D., R.D.G., J.K., C.L., M.A.N., N. Petousi, S.E.P., S.R.F.T., T.V. and M.P.W. were lead investigators on individual projects. H. Cario, M.F.M., C. Bento, K.D., O.D., R.D.G., D.J., C.L., D.N., E.O., A.B.O., M.P., A. Russo, E. Silverman, P.S.S., E. Sweeney, S.A.W. and M.P.W. contributed clinical samples and clinical data. C.A., M.A., A. Green, S.H., Z.K., S. Lamble, L.L., P.P., G.P.-E., A.T. and L.W. prepared libraries and generated whole-genome sequences, led by D. Buck (High-Throughput Genomics Group, Oxford) and D. Bentley (Illumina Cambridge). J. Becq, J. Broxholme, S.F., R.G., E.H., C.H., L.H., P.H., A.K., S. Lise, G.L., D.M., L.M., A. Rimmer, N.S., B.W., C.Y. and N. Popitsch performed study-wide bioinformatic analysis of whole-genome sequence data, led by J.-B.C. and R.R.C. J.T. performed the whole-exome sequence analysis presented in Supplementary Figure 10. E.E.D., A.V.G., M.H., J.L., H.C.M., S.J.M., K.A.M., A.P., L.Q. and P.A.v.S. performed project-specific bioinformatic analysis of whole-genome sequence data. A.R.A., O.C., A.L.F., A. Goriely, I.H.G., A.V.G., R.H., J.L., K.A.M. and A.P. performed project-specific genetic and functional validation studies. G.M. wrote the manuscript with help from H.C.M., J.C.T. and A.O.M.W. and further contributions from S. Lise, D.M., A.P., R.V.T. and S.E.P. J.C. collated information for the paper. P.D. chaired the Steering Committee and the Operations Committee. J.I.B., D. Bentley, G.M., P.J.R., J.C.T. and A.O.M.W. were members of the Steering Committee. J. Broxholme, D. Buck, J.-B.C., R.C., J.C.K., G.L., G.M., J.C.T., I.T., A.O.M.W. and L.W. were members of the Operations Committee.

Competing interests

All authors at Illumina are employees of Illumina, Inc., a public company that develops and markets systems for genetic analysis. G.M., G.L. and P.D. are founders and shareholders of Genomics, Ltd., a company that develops genome analytics.

Corresponding author

Correspondence to Gilean McVean.

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