Whole-genome sequencing of patients with rare diseases in a national health system,Nature

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Whole-genome sequencing of patients with rare diseases in a national health system
Nature ( IF 50.5 ) Pub Date : 2020-06-24 , DOI: 10.1038/s41586-020-2434-2
Ernest Turro _{1,

2,

3} , William J Astle _{3,

4} , Karyn Megy _{1,

2} , Stefan Gräf _{1,

2,

5} , Daniel Greene _{1,

3} , Olga Shamardina _{1,

2} , Hana Lango Allen _{1,

2} , Alba Sanchis-Juan _{1,

2} , Mattia Frontini _{1,

4,

6} , Chantal Thys ₇ , Jonathan Stephens _{1,

2} , Rutendo Mapeta _{1,

2} , Oliver S Burren _{5,

8} , Kate Downes _{1,

2} , Matthias Haimel _{1,

2,

5} , Salih Tuna _{1,

2} , Sri V V Deevi _{1,

2} , Timothy J Aitman _{9,

10} , David L Bennett _{11,

12} , Paul Calleja ₁₃ , Keren Carss _{1,

2} , Mark J Caulfield _{14,

15} , Patrick F Chinnery _{2,

16,

17} , Peter H Dixon ₁₈ , Daniel P Gale _{19,

20} , Roger James _{1,

2} , Ania Koziell _{21,

22} , Michael A Laffan _{23,

24} , Adam P Levine ₁₉ , Eamonn R Maher _{25,

26,

27} , Hugh S Markus ₂₈ , Joannella Morales ₂₉ , Nicholas W Morrell _{2,

5} , Andrew D Mumford _{30,

31} , Elizabeth Ormondroyd _{12,

32} , Stuart Rankin ₁₃ , Augusto Rendon _{1,

14} , Sylvia Richardson ₃ , Irene Roberts _{12,

33,

34} , Noemi B A Roy _{12,

33,

35} , Moin A Saleem _{36,

37} , Kenneth G C Smith _{5,

8} , Hannah Stark _{2,

38} , Rhea Y Y Tan ₂₈ , Andreas C Themistocleous ₁₁ , Adrian J Thrasher ₃₉ , Hugh Watkins _{32,

35,

40} , Andrew R Webster _{41,

42} , Martin R Wilkins ₄₃ , Catherine Williamson _{18,

44} , James Whitworth _{25,

26,

27} , Sean Humphray ₄₅ , David R Bentley ₄₅ , , Nathalie Kingston _{1,

2} , Neil Walker _{1,

2} , John R Bradley _{2,

5,

26,

46,

47} , Sofie Ashford _{2,

38} , Christopher J Penkett _{1,

2} , Kathleen Freson ₇ , Kathleen E Stirrups _{1,

2} , F Lucy Raymond _{2,

25} , Willem H Ouwehand _{1,

2,

4,

6,

48}

Affiliation

Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
NIHR BioResource, Cambridge University Hospitals NHS Foundation, Cambridge Biomedical Campus, Cambridge, UK.
MRC Biostatistics Unit, Cambridge Institute of Public Health, University of Cambridge, Cambridge, UK.
NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK.
Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
British Heart Foundation Cambridge Centre of Excellence, University of Cambridge, Cambridge, UK.
Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium.
Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK.
MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, UK.
Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
The Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
NIHR Oxford Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK.
High Performance Computing Service, University of Cambridge, Cambridge, UK.
Genomics England Ltd, London, UK.
William Harvey Research Institute, NIHR Biomedical Research Centre at Barts, Queen Mary University of London, London, UK.
Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
Medical Research Council Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge, UK.
Women and Children's Health, School of Life Course Sciences, King's College London, London, UK.
Department of Renal Medicine, University College London, London, UK.
Rare Renal Disease Registry, UK Renal Registry, Bristol, UK.
King's College London, London, UK.
Department of Paediatric Nephrology, Evelina London Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, UK.
Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.
Centre for Haematology, Imperial College London, London, UK.
Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
NIHR Cambridge Biomedical Research Centre, Cambridge Biomedical Campus, Cambridge, UK.
Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge, UK.
Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Bristol, UK.
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Cambridge, UK.
School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
Department of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Department of Paediatrics, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Bristol Renal and Children's Renal Unit, Bristol Medical School, University of Bristol, Bristol, UK.
Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
UCL Great Ormond Street Institute of Child Health, London, UK.
Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
Moorfields Eye Hospital NHS Trust, London, UK.
UCL Institute of Opthalmology, University College London, London, UK.
Department of Medicine, Imperial College London, London, UK.
Institute of Reproductive and Developmental Biology, Department of Surgery and Cancer, Faculty of Medicine, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.
Illumina Cambridge, Little Chesterford, UK.
Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Department of Renal Medicine, Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Wellcome Sanger Institute, Cambridge, UK.

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered 1 . Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants 2 , we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B , GATA1 , LRBA and MPL . Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare. Whole-genome sequencing and phenotype data sharing are introduced in a national health system to streamline diagnosis and to discover coding and non-coding variants that cause rare diseases.

中文翻译：

国家卫生系统罕见病患者的全基因组测序

大多数罕见病患者没有接受分子诊断，并且一半以上此类疾病的病因变异和致病基因仍有待发现 1 。在这里，我们在国家卫生系统中使用全基因组测序（WGS）来简化诊断并发现基因组编码和非编码区域中未知的病因变异。我们为 13,037 名参与者生成了 WGS 数据，其中 9,802 名参与者患有罕见疾病，并为 7,065 名广泛表型参与者中的 1,138 名提供了基因诊断。我们确定了基因与罕见疾病之间的 95 种孟德尔关联，其中 11 种是自 2015 年以来发现的，至少 79 种被确认为病因学关联。通过生成英国生物银行参与者的全基因组测序数据 2 ，我们发现稀有等位基因可以解释某些个体在红细胞数量性状尾部的存在。最后，我们发现了四种新的非编码变异，它们通过破坏 ARPC1B、GATA1、LRBA 和 MPL 的转录而导致疾病。我们的研究证明了在常规医疗保健中使用 WGS 进行诊断和病因发现的协同作用。国家卫生系统引入全基因组测序和表型数据共享，以简化诊断并发现导致罕见疾病的编码和非编码变异。

更新日期：2020-06-24

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