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Nat Genet. 2015 Jul;47(7):717-26. doi: 10.1038/ng.3304. Epub 2015 May 18.

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

Author information

1
1] National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Oxford, UK. [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
2
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
3
Centre for Computational Biology, University of Birmingham, Edgbaston, UK.
4
Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
5
Illumina Cambridge, Ltd., Saffron Walden, UK.
6
Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
7
Hematology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
8
Molecular Haematology Department, Oxford University Hospitals National Health Service (NHS) Trust, Oxford, UK.
9
Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.
10
1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. [2] Centre for Cellular and Molecular Physiology, University of Oxford, Oxford, UK.
11
Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, UK.
12
Department of Pediatrics and Adolescent Medicine, University Medical Center, Ulm, Germany.
13
Primary Immunodeficiency Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
14
Centre for Cellular and Molecular Physiology, University of Oxford, Oxford, UK.
15
1] Centre de Génétique Humaine, Institut de Génétique et de Pathologie, Gosselies, Belgium. [2] Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.
16
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
17
Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
18
Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
19
University Hospital Southampton NHS Foundation Trust, University of Southampton, Southampton, UK.
20
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
21
1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. [2] Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
22
1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. [2] Department of Statistics, University of Oxford, Oxford, UK.
23
Craniofacial Unit, Department of Plastic and Reconstructive Surgery, Oxford University Hospitals NHS Trust, Oxford, UK.
24
Oxford Laboratory for Integrative Physiology, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.
25
Kidney Diseases, Feinberg School of Medicine, Northwestern University and the Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
26
Centre for Cancer Research and Cell Biology, Queen's University, Belfast, UK.
27
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
28
Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.
29
Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College, London, UK.
30
Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Copenhagen, Denmark.
31
Department of Haematology, Belfast City Hospital, Belfast, UK.
32
Nuffield Department of Medicine, University of Oxford, Oxford, UK.
33
Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
34
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
35
Department of Pediatrics, University Hospital, Mainz, Germany.
36
1] National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Oxford, UK. [2] Department of Oncology, University of Oxford, Oxford, UK.
37
Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada.
38
1] MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. [2] Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
39
Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
40
1] National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Oxford, UK. [2] Oxford NHS Regional Molecular Genetics Laboratory, Oxford University Hospitals NHS Trust, Oxford, UK.
41
Division of Genetics, King's College London, Guy's Hospital, London, UK.
42
Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, Missouri, USA.
43
Office of the Regius Professor of Medicine, University of Oxford, Oxford, UK.

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.

PMID:
25985138
PMCID:
PMC4601524
DOI:
10.1038/ng.3304
[Indexed for MEDLINE]
Free PMC Article

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