title: Molecular findings from 537 individuals with inherited retinal disease.
abstract: BACKGROUND
  Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous set of disorders, for which diagnostic second-generation sequencing (next-generation sequencing, NGS) services have been developed worldwide.
  
  
  METHODS
  We present the molecular findings of 537 individuals referred to a 105-gene diagnostic NGS test for IRDs. We assess the diagnostic yield, the spectrum of clinical referrals, the variant analysis burden and the genetic heterogeneity of IRD. We retrospectively analyse disease-causing variants, including an assessment of variant frequency in Exome Aggregation Consortium (ExAC).
  
  
  RESULTS
  Individuals were referred from 10 clinically distinct classifications of IRD. Of the 4542 variants clinically analysed, we have reported 402 mutations as a cause or a potential cause of disease in 62 of the 105 genes surveyed. These variants account or likely account for the clinical diagnosis of IRD in 51% of the 537 referred individuals. 144 potentially disease-causing mutations were identified as novel at the time of clinical analysis, and we further demonstrate the segregation of known disease-causing variants among individuals with IRD. We show that clinically analysed variants indicated as rare in dbSNP and the Exome Variant Server remain rare in ExAC, and that genes discovered as a cause of IRD in the post-NGS era are rare causes of IRD in a population of clinically surveyed individuals.
  
  
  CONCLUSIONS
  Our findings illustrate the continued powerful utility of custom-gene panel diagnostic NGS tests for IRD in the clinic, but suggest clear future avenues for increasing diagnostic yields.
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.|Institute of Human Development, University of Manchester, Manchester, UK.
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Ellingford
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Barton
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Bhaskar
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.|Institute of Human Development, University of Manchester, Manchester, UK.
authors.forename: James
authors.initials: J
authors.lastname: O'Sullivan
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Williams
authors.affiliation: Institute of Population Health, University of Manchester, Manchester, UK.
authors.forename: Janine A
authors.initials: JA
authors.lastname: Lamb
authors.affiliation: Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, India.
authors.forename: Binay
authors.initials: B
authors.lastname: Panda
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.|Institute of Human Development, University of Manchester, Manchester, UK.|Manchester Royal Eye Hospital, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Panagiotis I
authors.initials: PI
authors.lastname: Sergouniotis
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.|Institute of Human Development, University of Manchester, Manchester, UK.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Gillespie
authors.affiliation: School of Public Health, University of Texas Health Science Center, Houston, Texas, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Daiger
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.
authors.forename: Georgina
authors.initials: G
authors.lastname: Hall
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.
authors.forename: Theodora
authors.initials: T
authors.lastname: Gale
authors.affiliation: Institute of Human Development, University of Manchester, Manchester, UK.|Manchester Royal Eye Hospital, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: I Christopher
authors.initials: IC
authors.lastname: Lloyd
authors.affiliation: Institute of Human Development, University of Manchester, Manchester, UK.|Manchester Royal Eye Hospital, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Bishop
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Ramsden
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.|Institute of Human Development, University of Manchester, Manchester, UK.|Manchester Royal Eye Hospital, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Graeme C M
authors.initials: GCM
authors.lastname: Black
keywords: Molecular genetics; bioinformatics; inherited retinal dystrophy; next-generation sequencing; retinitis pigmentosa