Molecular findings from 537 individuals with inherited retinal disease
Ellingford, Jamie M ...
Background Inherited retinal diseases (IRDs) are aclinically 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 testfor IRDs. We assess the diagnostic yield, the spectrum ofclinical referrals, the variant analysis burden and thegenetic heterogeneity of IRD. We retrospectively analyse disease-causing variants, including an assessment ofvariant 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 acause 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 537referred 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 indicatedas rare in dbSNP and the Exome Variant Server remainrare in ExAC, and that genes discovered as a cause of IRD in the post-NGS era are rare causes of IRD in apopulation of clinically surveyed individuals. ConclusionsOur 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.
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