10 万基因组计划在医疗保健中的罕见病诊断 - 初步报告。
100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.
机构信息
From Genomics England (D.S., K.R.S., A.M., E.A.T., E.M.M., A.T., G.C., K.I., L.M., M. Wielscher, A.N., M. Bale, E.B., C.B., H.B., M. Bleda, A. Devereau, D.H., E. Haraldsdottir, Z.H., D.K., C. Patch, D.P., A.M., R. Sultana, M.R., A.L.T.T., C. Tregidgo, C. Turnbull, M. Welland, S. Wood, C.S., E.W., S.L., R.E.F., L.C.D., O.N., I.U.S.L., C.F.W., J.C., R.H.S., T.F., A.R., M.C.), the William Harvey Research Institute, Queen Mary University of London (D.S., K.R.S., V.C., A.T., L.M., M.R.B., D.K., S. Wood, P.C., J.O.J., T.F., M.C.), University College London (UCL) Institute of Ophthalmology (V.C., G.A., M.M., A.T.M., S. Malka, N.P., P.Y.-W.-M., A.R.W.), UCL Genetics Institute (V.C., N.W.W.), GOSgene (H.J.W.), Genetics and Genomic Medicine Programme (L.V., M.R., M.D., L.C., P. Beales, M.B.-G.), National Institute for Health Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre (BRC) (M.R., S. Grunewald, S.C.-L., F.M., C. Pilkington, L.R.W., L.C., P. Beales, M.B.-G.), Infection, Immunity, and Inflammation Research and Teaching Department (P.A., L.R.W.), Stem Cells and Regenerative Medicine (N.T.), and Mitochondrial Research Group (S. Rahman), UCL Great Ormond Street Institute of Child Health, UCL Ear Institute (L.V.), the Department of Renal Medicine (D. Bockenhauer), and Institute of Cardiovascular Science (P.E.), UCL, Moorfields Eye Hospital National Health Service (NHS) Foundation Trust (V.C., G.A., M.M., A.T.M., S. Malka, N.P., A.R.W.), the National Hospital for Neurology and Neurosurgery (J.V., E.O., J.Y., K. Newland, H.R.M., J.P., N.W.W., H.H.), the Metabolic Unit (L.A., S. Grunewald, S. Rahman), London Centre for Paediatric Endocrinology and Diabetes (M.D.), and the Department of Gastroenterology (N.T.), Great Ormond Street Hospital for Children NHS Foundation Trust (L.V., D. Bockenhauer, A. Broomfield, M.A.C., T. Lam, E.F., V.G., S.C.-L., F.M., C. Pilkington, R. Quinlivan, C.W., L.R.W., A. Worth, L.C., P. Beales, M.B.-G., R.H.S.), the Clinical Genetics Department (M.R., T.B., C. Compton, C.D., E. Haque, L.I., D.J., S. Mohammed, L.R., S. Rose, D.R., G.S., A.C.S., F.F., M.I.) and St. John's Institute of Dermatology (H.F., R. Sarkany), Guy's and St. Thomas' NHS Foundation Trust, the Division of Genetics and Epidemiology, Institute of Cancer Research (C. Turnbull), Florence Nightingale Faculty of Nursing, Midwifery, and Palliative Care (T.B.), Division of Genetics and Molecular Medicine (M.A.S.), and Division of Medical and Molecular Genetics (M.I.), King's College London, NIHR BRC at Moorfields Eye Hospital (P.Y.-W.-M.), NHS England and NHS Improvement, Skipton House (V.D., A. Douglas, S. Hill), and Imperial College Healthcare NHS Trust, Hammersmith Hospital (K. Naresh), London, Open Targets and European Molecular Biology Laboratory-European Bioinformatics Institute, Wellcome Genome Campus, Hinxton (E.M.M.), the Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine, and Health, University of Manchester (J.M.E., S.B., J.C.-S., S.D., G.H., H.B.T., R.T.O., G. Black, W.N.), and the Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University NHS Foundation Trust (J.M.E., Z.H., S.B., J.C.-S., S.D., G.H., G. Black, W.N.), Manchester, the Department of Genetic and Genomic Medicine, Institute of Medical Genetics, Cardiff University, Cardiff (H.J.W.), the Department of Clinical Neurosciences (T.R., W.W., R.H., P.F.C.), the Medical Research Council (MRC) Mitochondrial Biology Unit (T.R., W.W., P.Y.-W.-M., P.F.C.), the Department of Paediatrics (T.R.), the Department of Haematology (K.S., C. Penkett, S. Gräf, R.M., W.H.O., A.R.), the School of Clinical Medicine (K.R., E.L., R.A.F., K.P., F.L.R.), the Department of Medicine (S. Gräf), and Cambridge Centre for Brain Repair, Department of Clinical Neurosciences (P.Y.-W.-M.), University of Cambridge, NIHR BioResource, Cambridge University Hospitals (K.S., S.A., R.J., C. Penkett, E.D., S. Gräf, R.M., M.K., J.R.B., P.F.C., W.H.O., F.L.R.), and Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust (G.F., P.T., O.S.-B., S. Halsall, K.P., A. Wagner, S.G.M., N.B., M.K.), Cambridge Biomedical Campus, Wellcome-MRC Institute of Metabolic Science and NIHR Cambridge BRC (M.G.), Congenica (A.H., H.S.), Illumina Cambridge (A. Wolejko, B.H., G. Burns, S. Hunter, R.J.G., S.J.H., D. Bentley), NHS Blood and Transplant (W.H.O.), and Wellcome Sanger Institute (W.H.O.), Cambridge, the Health Economics Research Centre (J. Buchanan, S. Wordsworth) and the Wellcome Centre for Human Genetics (C. Camps, J.C.T.), University of Oxford, NIHR Oxford BRC (J. Buchanan, S. Wordsworth, J.D., C. Crichton, J.W., K.W., C. Camps, S.P., N.B.A.R., A.S., J.T., J.C.T.), the Oxford Centre for Genomic Medicine (A. de Burca, A.H.N.), and the Departments of Haematology (N.B.A.R.) and Neurology (A.S.), Oxford University Hospitals NHS Foundation Trust, Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital (C. Campbell, K.G., T. Lester, J.T.), the MRC Weatherall Institute of Molecular Medicine (N.K., N.B.A.R., A.O.M.W.) and the Oxford Epilepsy Research Group (A.S.), Nuffield Department of Clinical Neurosciences (A.H.N.), University of Oxford, and the Department of Clinical Immunology (S.P.), John Radcliffe Hospital, Oxford, Peninsula Clinical Genetics Service, Royal Devon and Exeter NHS Foundation Trust (E.B.), and the University of Exeter Medical School (E.B., C.F.W.), Royal Devon and Exeter Hospital (S.E.), Exeter, Newcastle Eye Centre, Royal Victoria Infirmary (A.C.B.), the Institute of Genetic Medicine, Newcastle University, International Centre for Life (V.S., P. Brennan), Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University (G.S.G., R.H., A.M.S., D.M.T., R. Quinton, R.M., R.W.T., J.A.S.), Highly Specialised Mitochondrial Service (G.S.G., A.M.S., D.M.T., R.M., R.W.T.) and Northern Genetics Service (J. Burn), Newcastle upon Tyne Hospitals NHS Foundation Trust (J.A.S.), and NIHR Newcastle BRC (G.S.G., D.M.T., J.A.S.), Newcastle upon Tyne, the Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, University of Birmingham (C. Palles), and Birmingham Women's Hospital (D.M.), Birmingham, the Genomic Informatics Group (E.G.S.), University Hospital Southampton (I.K.T.), and the University of Southampton (I.K.T.), Southampton, Liverpool Women's NHS Foundation Trust, Liverpool (A. Douglas), the School of Cellular and Molecular Medicine, University of Bristol, Bristol (A.D.M.), and Yorkshire and Humber, Sheffield Children's Hospital, Sheffield (G.W.) - all in the United Kingdom; Fabric Genomics, Oakland (M. Babcock, M.G.R.), and the Ophthalmology Department, University of California, San Francisco School of Medicine, San Francisco (A.T.M.) - both in California; the Jackson Laboratory for Genomic Medicine, Farmington, CT (P.N.R.); and the Center for Genome Research and Biocomputing, Environmental and Molecular Toxicology, Oregon State University, Corvallis (M.H.).
出版信息
N Engl J Med. 2021 Nov 11;385(20):1868-1880. doi: 10.1056/NEJMoa2035790.
BACKGROUND
The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection.
METHODS
We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis.
RESULTS
Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives.
CONCLUSIONS
Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).
背景
英国的 10 万基因组计划正在调查在常规护理后对未确诊的罕见疾病患者进行基因组测序的作用，以及该研究与英国国民保健制度中医疗保健实施的一致性。该项目的其他部分侧重于癌症和感染患者。
方法
我们进行了一项试点研究，涉及来自 2183 个家庭的 4660 名参与者，其中存在 161 种涵盖广泛罕见疾病的疾病。我们使用人类表型本体论术语收集临床特征数据，进行基因组测序，根据应用的虚拟基因面板和表型对自动变体进行优先级排序，并通过研究分析确定新的致病性变体。
结果
家族结构之间的诊断率有所不同，在双亲加先证者的三联体家族和具有较大系谱的家族中最高。单基因病因可能性大的疾病（35%）的诊断率明显高于多基因病因可能性大的疾病（11%）。智力障碍、听力障碍和视力障碍的诊断率在 40%至 55%之间。我们在 25%的先证者中做出了遗传诊断。通过研究和自动方法的结合做出了 14%的诊断，这对于我们发现病因非编码、结构和线粒体基因组变体以及外显子组测序覆盖不佳的编码变体的情况至关重要。对 57000 个基因组进行全队列负担测试，发现了三个新的疾病基因和 19 个新的关联。我们做出的遗传诊断中有 25%对患者或其亲属的临床决策立即产生影响。
结论
我们在国家卫生保健系统中对基因组测序的试点研究表明，一系列罕见疾病的诊断率有所提高。（由英国国家卫生研究院和其他机构资助）。
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