Evaluation of Clinical Utility of Whole Genome Sequencing: the WGS500 Programme. J. Taylor1, G. McVean2, A. Wilkie3, J. Bell4, P. Ratcliffe5, D. Bentley6, P. Donnelly2, WGS500 Consortium 1) Oxford Biomedical Res Ctr, Wellcome Trust Genetic Ctr, Oxford, United Kingdom; 2) Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom; 3) Weatherall Institute of Molecular Medicine, Oxford, United Kingdom; 4) Office of Regius Professor, Richard Doll Building, Oxford, United Kingdom; 5) Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, Oxford, United Kingdom; 6) Illumina Inc, Chesterford Research Park, Little Chesterford, Essex, United Kingdom.

   Whole genome sequencing (WGS) has been successfully used in a research setting to identify novel genes underpinning disease, but evaluation of the utility of WGS in the clinic is in its infancy. However, WGS has the potential to improve diagnosis and treatment of a range of medical conditions and offers many advantages over current approaches of targeted and exome sequencing, particularly the comprehensive interrogation of all types of genetic variation it provides. Nonetheless, significant challenges must be addressed, including mechanisms for establishing pathogenicity for variants of unknown significance at scale and managing incidental findings. In order to evaluate the potential clinical utility of WGS, we sequenced 500 genomes from patients with 42 different disease types encompassing Mendelian & immunological disorders and cancer. Patients were pre-screened for known candidate genes and chromosomal imbalances as appropriate. Sequencing was conducted on HiSeq 2000 with bioinformatics analysis using a bespoke standardised pipeline to detect, genotype and deeply annotate variants, identify broad scale copy number variation and homozygosity. To date, this study has led to the identification of (i) several novel disease genes, such as POLD & POLE for inherited colorectal cancer, TCF12 for craniosynostosis and a gene of unknown function, C15orf41, for congenital dyserythropoietic anaemia; (ii) identification of novel disease mechanisms for epilepsy phenotypes; (iii) pathogenic variants in regulatory regions; (iv) complex structural rearrangements; and (v) novel phenotypes for known genes. WGS has had substantial clinical impact, including new molecular diagnoses for patients (25% Mendelian cases), more accurate reproductive risk counselling, change of patient diagnosis leading to altered treatment and inclusion of new genes on targeted diagnostic gene panels. We will describe the general lessons learned from clinical sequencing on this scale, from bioinformatics and analysis, through the challenges of establishing pathogenicity, to clinical impact and the practicalities of introducing WGS into the clinic, including the ethical, legal and health economic dimensions, and will illustrate these with case studies. The UK Government recently announced the whole genome sequencing of 100,000 patients in the National Health Service (the UKs single healthcare provider). Our study represents a natural pilot of this approach in the UK context.

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