RT Journal Article
SR Electronic
T1 Molecular findings from 537 individuals with inherited retinal disease
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 761
OP 767
DO 10.1136/jmedgenet-2016-103837
VO 53
IS 11
A1 Jamie M Ellingford
A1 Stephanie Barton
A1 Sanjeev Bhaskar
A1 James O'Sullivan
A1 Simon G Williams
A1 Janine A Lamb
A1 Binay Panda
A1 Panagiotis I Sergouniotis
A1 Rachel L Gillespie
A1 Stephen P Daiger
A1 Georgina Hall
A1 Theodora Gale
A1 I Christopher Lloyd
A1 Paul N Bishop
A1 Simon C Ramsden
A1 Graeme C M Black
YR 2016
UL http://jmg.bmj.com/content/53/11/761.abstract
AB 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.