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Ellingford JM, Barton S, Bhaskar S, et al. Molecular findings from 537 individuals with inherited retinal disease. J Med Genet. 2016;53(11):761-767doi: 10.1136/jmedgenet-2016-103837.
Ellingford, J. M., Barton, S., Bhaskar, S., O'Sullivan, J., Williams, S. G., Lamb, J. A., Panda, B., Sergouniotis, P. I., Gillespie, R. L., Daiger, S. P., Hall, G., Gale, T., Lloyd, I. C., Bishop, P. N., Ramsden, S. C., & Black, G. C. M. (2016). Molecular findings from 537 individuals with inherited retinal disease. Journal of medical genetics, 53(11), 761-767. https://doi.org/10.1136/jmedgenet-2016-103837
Ellingford, Jamie M, et al. "Molecular findings from 537 individuals with inherited retinal disease." Journal of medical genetics vol. 53,11 (2016): 761-767. doi: https://doi.org/10.1136/jmedgenet-2016-103837
Ellingford JM, Barton S, Bhaskar S, O'Sullivan J, Williams SG, Lamb JA, Panda B, Sergouniotis PI, Gillespie RL, Daiger SP, Hall G, Gale T, Lloyd IC, Bishop PN, Ramsden SC, Black GCM. Molecular findings from 537 individuals with inherited retinal disease. J Med Genet. 2016 Nov;53(11):761-767. doi: 10.1136/jmedgenet-2016-103837. Epub 2016 May 11. PMID: 27208204; PMCID: PMC5106339.
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J Med Genet. 2016 Nov;53(11):761-767. doi: 10.1136/jmedgenet-2016-103837. Epub 2016 May 11.

Molecular findings from 537 individuals with inherited retinal disease.

Journal of medical genetics

Jamie M Ellingford, Stephanie Barton, Sanjeev Bhaskar, James O'Sullivan, Simon G Williams, Janine A Lamb, Binay Panda, Panagiotis I Sergouniotis, Rachel L Gillespie, Stephen P Daiger, Georgina Hall, Theodora Gale, I Christopher Lloyd, Paul N Bishop, Simon C Ramsden, Graeme C M Black

Affiliations

  1. Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK.
  2. Institute of Human Development, University of Manchester, Manchester, UK.
  3. Institute of Population Health, University of Manchester, Manchester, UK.
  4. Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, India.
  5. Manchester Royal Eye Hospital, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
  6. School of Public Health, University of Texas Health Science Center, Houston, Texas, USA.

PMID: 27208204 PMCID: PMC5106339 DOI: 10.1136/jmedgenet-2016-103837

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.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Keywords: Molecular genetics; bioinformatics; inherited retinal dystrophy; next-generation sequencing; retinitis pigmentosa

Conflict of interest statement

Competing interests: None declared.

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