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Am J Hum Genet. 2017 Jan 5;100(1):75-90. doi: 10.1016/j.ajhg.2016.12.003. Epub 2016 Dec 29.

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.

Collaborators (274)

Aitman T, Alachkar H, Ali S, Allen L, Allsup D, Ambegaonkar G, Anderson J, Antrobus R, Armstrong R, Arno G, Arumugakani G, Ashford S, Astle W, Attwood A, Austin S, Bacchelli C, Bakchoul T, Bariana TK, Baxendale H, Bennett D, Bethune C, Bibi S, Bitner-Glindzicz M, Bleda M, Boggard H, Bolton-Maggs P, Booth C, Bradley JR, Brady A, Brown M, Browning M, Bryson C, Burns S, Calleja P, Canham N, Carmichael J, Carss K, Caulfield M, Chalmers E, Chandra A, Chinnery P, Chitre M, Church C, Clement E, Clements-Brod N, Clowes V, Coghlan G, Collins P, Cooper N, Creaser-Myers A, DaCosta R, Daugherty L, Davies S, Davis J, De Vries M, Deegan P, Deevi SVV, Deshpande C, Devlin L, Dewhurst E, Doffinger R, Dormand N, Drewe E, Edgar D, Egner W, Erber WN, Erwood M, Everington T, Favier R, Firth H, Fletcher D, Flinter F, Fox JC, Frary A, Freson K, Furie B, Furnell A, Gale D, Gardham A, Gattens M, Ghali N, Ghataorhe PK, Ghurye R, Gibbs S, Gilmour K, Gissen P, Goddard S, Gomez K, Gordins P, Gräf S, Greene D, Greenhalgh A, Greinacher A, Grigoriadou S, Grozeva D, Hackett S, Hadinnapola C, Hague R, Haimel M, Halmagyi C, Hammerton T, Hart D, Hayman G, Heemskerk JWM, Henderson R, Hensiek A, Henskens Y, Herwadkar A, Holden S, Holder M, Holder S, Hu F, Huissoon A, Humbert M, Hurst J, James R, Jolles S, Josifova D, Kazmi R, Keeling D, Kelleher P, Kelly AM, Kennedy F, Kiely D, Kingston N, Koziell A, Krishnakumar D, Kuijpers TW, Kumararatne D, Kurian M, Laffan MA, Lambert MP, Allen HL, Lawrie A, Lear S, Lees M, Lentaigne C, Liesner R, Linger R, Longhurst H, Lorenzo L, Machado R, Mackenzie R, MacLaren R, Maher E, Maimaris J, Mangles S, Manson A, Mapeta R, Markus HS, Martin J, Masati L, Mathias M, Matser V, Maw A, McDermott E, McJannet C, Meacham S, Meehan S, Megy K, Mehta S, Michaelides M, Millar CM, Moledina S, Moore A, Morrell N, Mumford A, Murng S, Murphy E, Nejentsev S, Noorani S, Nurden P, Oksenhendler E, Ouwehand WH, Papadia S, Park SM, Parker A, Pasi J, Patch C, Paterson J, Payne J, Peacock A, Peerlinck K, Penkett CJ, Pepke-Zaba J, Perry DJ, Pollock V, Polwarth G, Ponsford M, Qasim W, Quinti I, Rankin S, Rankin J, Raymond FL, Rehnstrom K, Reid E, Rhodes CJ, Richards M, Richardson S, Richter A, Roberts I, Rondina M, Rosser E, Roughley C, Rue-Albrecht K, Samarghitean C, Sanchis-Juan A, Sandford R, Santra S, Sargur R, Savic S, Schulman S, Schulze H, Scott R, Scully M, Seneviratne S, Sewell C, Shamardina O, Shipley D, Simeoni I, Sivapalaratnam S, Smith K, Sohal A, Southgate L, Staines S, Staples E, Stauss H, Stein P, Stephens J, Stirrups K, Stock S, Suntharalingam J, Tait RC, Talks K, Tan Y, Thachil J, Thaventhiran J, Thomas E, Thomas M, Thompson D, Thrasher A, Tischkowitz M, Titterton C, Toh CH, Toshner M, Treacy C, Trembath R, Tuna S, Turek W, Turro E, Van Geet C, Veltman M, Vogt J, von Ziegenweldt J, Vonk Noordegraaf A, Wakeling E, Wanjiku I, Warner TQ, Wassmer E, Watkins H, Webster A, Welch S, Westbury S, Wharton J, Whitehorn D, Wilkins M, Willcocks L, Williamson C, Woods G, Wort J, Yeatman N, Yong P, Young T, Yu P.

Author information

1
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.
2
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.
3
UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
4
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.
5
University College London Genetics Institute, London WC1E 6BT, UK.
6
Moorfields Eye Hospital, London EC1V 2PD, UK.
7
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.
8
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.
9
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.
10
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.
11
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.
12
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.
13
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.
14
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.
15
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.
16
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.
17
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.
18
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 School of Medicine, University of California San Francisco, San Francisco, CA 94158, USA.
19
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.

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.

KEYWORDS:

copy-number variants; rare sequence variant; retinal dystrophy; whole-genome sequence

PMID:
28041643
PMCID:
PMC5223092
DOI:
10.1016/j.ajhg.2016.12.003
[Indexed for MEDLINE]
Free PMC Article

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