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.