title: Factors influencing success of clinical genome sequencing across a broad spectrum of disorders.
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.
authors.affiliation: NIHR Comprehensive Biomedical Research Centre, Oxford, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.initials: JC
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.initials: JB
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.lastname: Allan
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
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authors.affiliation: Illumina Cambridge Limited, Saffron Walden, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|Centre for Cellular and Molecular Physiology, University of Oxford, Oxford, UK.
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authors.affiliation: NIHR Comprehensive Biomedical Research Centre, Oxford, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Centre for Cellular and Molecular Physiology, University of Oxford, Oxford, UK.
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authors.affiliation: NIHR Comprehensive Biomedical Research Centre, Oxford, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
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authors.affiliation: Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|Department of Statistics, University of Oxford, Oxford, UK.
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authors.affiliation: NIHR Comprehensive Biomedical Research Centre, Oxford, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
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authors.affiliation: NIHR Comprehensive Biomedical Research Centre, Oxford, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: NIHR Comprehensive Biomedical Research Centre, Oxford, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: NIHR Comprehensive Biomedical Research Centre, Oxford, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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authors.affiliation: Illumina Cambridge Limited, Saffron Walden, UK.
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authors.initials: JI
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authors.affiliation: Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|Department of Statistics, University of Oxford, Oxford, UK.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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mesh_terms: D001483:Base Sequence; D004252:DNA Mutational Analysis; D030342:Genetic Diseases, Inborn / Q000175:diagnosis* / Q000235:genetics; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D025202:Molecular Diagnostic Techniques; D058977:Molecular Sequence Annotation; D020641:Polymorphism, Single Nucleotide; D012680:Sensitivity and Specificity