Molecular findings from 537 individuals with inherited retinal disease

Research output: Contribution to journalArticle

  • External authors:
  • Jamie Ellingford
  • Stephanie Barton
  • Sanjeev Bhaskar
  • Binay Panda
  • Stephen Daiger
  • Georgina Hall
  • Theodora Gale
  • Christopher Lloyd
  • Paul Bishop
  • Simon Ramsden
  • Graeme Black

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.

Bibliographical metadata

Original languageEnglish
Pages (from-to)761-767
Number of pages7
JournalJournal of Medical Genetics
Volume53
Issue number11
Early online date11 May 2016
DOIs
Publication statusPublished - Nov 2016

Related information

Researchers

View all