title: Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.
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.
authors.affiliation: 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.
authors.forename: Keren J
authors.initials: KJ
authors.lastname: Carss
authors.affiliation: 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.
authors.forename: Gavin
authors.initials: G
authors.lastname: Arno
authors.affiliation: 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.
authors.forename: Marie
authors.initials: M
authors.lastname: Erwood
authors.affiliation: 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.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Stephens
authors.affiliation: 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.
authors.forename: Alba
authors.initials: A
authors.lastname: Sanchis-Juan
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hull
authors.affiliation: 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.
authors.forename: Karyn
authors.initials: K
authors.lastname: Megy
authors.affiliation: 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.
authors.forename: Detelina
authors.initials: D
authors.lastname: Grozeva
authors.affiliation: 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.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Dewhurst
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
authors.forename: Samantha
authors.initials: S
authors.lastname: Malka
authors.affiliation: University College London Genetics Institute, London WC1E 6BT, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: 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.
authors.forename: Christopher
authors.initials: C
authors.lastname: Penkett
authors.affiliation: 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.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Stirrups
authors.affiliation: Moorfields Eye Hospital, London EC1V 2PD, UK.
authors.forename: Roberta
authors.initials: R
authors.lastname: Rizzo
authors.affiliation: Moorfields Eye Hospital, London EC1V 2PD, UK.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Wright
authors.affiliation: 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.
authors.forename: Dragana
authors.initials: D
authors.lastname: Josifova
authors.affiliation: 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.
authors.forename: Maria
authors.initials: M
authors.lastname: Bitner-Glindzicz
authors.affiliation: 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.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Scott
authors.affiliation: 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.
authors.forename: Emma
authors.initials: E
authors.lastname: Clement
authors.affiliation: 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.
authors.forename: Louise
authors.initials: L
authors.lastname: Allen
authors.affiliation: 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.
authors.forename: Ruth
authors.initials: R
authors.lastname: Armstrong
authors.affiliation: 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.
authors.forename: Angela F
authors.initials: AF
authors.lastname: Brady
authors.affiliation: 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.
authors.forename: Jenny
authors.initials: J
authors.lastname: Carmichael
authors.affiliation: 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.
authors.forename: Manali
authors.initials: M
authors.lastname: Chitre
authors.affiliation: 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.
authors.forename: Robert H H
authors.initials: RHH
authors.lastname: Henderson
authors.affiliation: 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.
authors.forename: Jane
authors.initials: J
authors.lastname: Hurst
authors.affiliation: 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.
authors.forename: Robert E
authors.initials: RE
authors.lastname: MacLaren
authors.affiliation: 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.
authors.forename: Elaine
authors.initials: E
authors.lastname: Murphy
authors.affiliation: 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.
authors.forename: Joan
authors.initials: J
authors.lastname: Paterson
authors.affiliation: 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.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Rosser
authors.affiliation: 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.
authors.forename: Dorothy A
authors.initials: DA
authors.lastname: Thompson
authors.affiliation: 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.
authors.forename: Emma
authors.initials: E
authors.lastname: Wakeling
authors.affiliation: 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.
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.affiliation: 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.
authors.forename: Michel
authors.initials: M
authors.lastname: Michaelides
authors.affiliation: 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.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.affiliation: 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.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
authors.affiliation: 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.
authors.forename: F Lucy
authors.initials: FL
authors.lastname: Raymond
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000483:Alleles; D001483:Base Sequence; D015794:Choroideremia / Q000235:genetics; D004252:DNA Mutational Analysis; D005006:Ethnicity / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D009154:Mutation; D035583:Rare Diseases / Q000235:genetics; D012164:Retinal Diseases / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C081787:CHM protein, human
keywords: copy-number variants; rare sequence variant; retinal dystrophy; whole-genome sequence