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. 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

Jamie M Ellingford  1   2 , Stephanie Barton  1 , Sanjeev Bhaskar  1 , James O'Sullivan  1   2 , Simon G Williams  1 , Janine A Lamb  3 , Binay Panda  4 , Panagiotis I Sergouniotis  1   2   5 , Rachel L Gillespie  1   2 , Stephen P Daiger  6 , Georgina Hall  1 , Theodora Gale  1 , I Christopher Lloyd  2   5 , Paul N Bishop  2   5 , Simon C Ramsden  1 , Graeme C M Black  1   2   5
Affiliations

Molecular findings from 537 individuals with inherited retinal disease

Jamie M Ellingford et al. J Med Genet. 2016 Nov.

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.

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

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Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
The variant analysis burden. The numbers of variants analysed by clinically accredited scientists by their expected consequences on the encoded protein and frequency in control populations. Annotations are performed against the specified transcripts in online supplementary table S1 using V.68 of the Ensembl database and population frequencies available in dbSNP and EVS.
Figure 2
Figure 2
The genetic basis of inherited retinal disease in 271 individuals with a confirmed or provisional molecular diagnosis. Each segment illustrates the number of individuals with genetic variants determined as a cause of inherited retinal disease.
Figure 3
Figure 3
The relationship between the genes accounting for molecular diagnoses and the year of their discovery. The curves illustrate the trends in the proportion of 271 molecular diagnoses accounted for by the analysis of 105 genes through diagnostic next-generation sequencing.
See this image and copyright information in PMC

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