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Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.
Carss, Keren J; Arno, Gavin; Erwood, Marie; Stephens, Jonathan; Sanchis-Juan, Alba; Hull, Sarah; Megy, Karyn; Grozeva, Detelina; Dewhurst, Eleanor; Malka, Samantha; Plagnol, Vincent; Penkett, Christopher; Stirrups, Kathleen; Rizzo, Roberta; Wright, Genevieve; Josifova, Dragana; Bitner-Glindzicz, Maria; Scott, Richard H; Clement, Emma; Allen, Louise; Armstrong, Ruth; Brady, Angela F; Carmichael, Jenny; Chitre, Manali; Henderson, Robert H H; Hurst, Jane; MacLaren, Robert E; Murphy, Elaine; Paterson, Joan; Rosser, Elisabeth; Thompson, Dorothy A; Wakeling, Emma; Ouwehand, Willem H; Michaelides, Michel; Moore, Anthony T; Webster, Andrew R; Raymond, F Lucy.
Afiliação
  • Carss KJ; Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge CB2 0PT, UK; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
  • Arno G; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
  • Erwood M; Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge CB2 0PT, UK; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
  • Stephens J; Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge CB2 0PT, UK; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
  • Sanchis-Juan A; Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge CB2 0PT, UK; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
  • Hull S; UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
  • Megy K; Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge CB2 0PT, UK; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
  • Grozeva D; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
  • Dewhurst E; Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge CB2 0PT, UK; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
  • Malka S; UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
  • Plagnol V; University College London Genetics Institute, London WC1E 6BT, UK.
  • Penkett C; Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge CB2 0PT, UK; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
  • Stirrups K; Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge CB2 0PT, UK; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
  • Rizzo R; Moorfields Eye Hospital, London EC1V 2PD, UK.
  • Wright G; Moorfields Eye Hospital, London EC1V 2PD, UK.
  • Josifova D; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Clinical Genetics Department, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
  • Bitner-Glindzicz M; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
  • Scott RH; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; North East Thames Regional Genetics Service, Great Ormond Street Hospital, London WC1N 3JH, UK.
  • Clement E; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Great Ormond Street Hospital for Children, Great Ormond Street, London WC1N 3JH, UK.
  • Allen L; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Department of Ophthalmology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
  • Armstrong R; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Departments of Medical Genetics and Paediatric Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
  • Brady AF; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Watford Road, Harrow HA1 3UJ, UK.
  • Carmichael J; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Departments of Medical Genetics and Paediatric Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
  • Chitre M; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Departments of Medical Genetics and Paediatric Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
  • Henderson RHH; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Moorfields Eye Hospital, London EC1V 2PD, UK; Great Ormond Street Hospital for Children, Great Ormond Street, London WC1N 3JH, UK.
  • Hurst J; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Great Ormond Street Hospital for Children, Great Ormond Street, London WC1N 3JH, UK.
  • MacLaren RE; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Moorfields Eye Hospital, London EC1V 2PD, UK; Nuffield Laboratory of Ophthalmology, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
  • Murphy E; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
  • Paterson J; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Departments of Medical Genetics and Paediatric Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
  • Rosser E; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Great Ormond Street Hospital for Children, Great Ormond Street, London WC1N 3JH, UK.
  • Thompson DA; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Clinical and Academic Department of Ophthalmology, Great Ormond Street Hospital for Children, London WC1N 3JH, UK.
  • Wakeling E; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Watford Road, Harrow HA1 3UJ, UK.
  • Ouwehand WH; Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge CB2 0PT, UK; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
  • Michaelides M; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
  • Moore AT; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK; Ophthalmology Department, UCSF Scho
  • Webster AR; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
  • Raymond FL; NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK. Electronic address: flr24@cam.ac.uk.
Am J Hum Genet ; 100(1): 75-90, 2017 01 05.
Article em En | MEDLINE | ID: mdl-28041643
ABSTRACT
Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doenças Retinianas / Variação Genética / Análise Mutacional de DNA / Genoma Humano Idioma: En Ano de publicação: 2017 Tipo de documento: Article
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doenças Retinianas / Variação Genética / Análise Mutacional de DNA / Genoma Humano Idioma: En Ano de publicação: 2017 Tipo de documento: Article