Abstract
Inherited retinal diseases (IRDs) are a common cause of visual impairment. IRD covers a set of genetically highly heterogeneous disorders with more than 150 genes associated with one or more clinical forms of IRD. Molecular genetic diagnosis has become increasingly important especially due to expanding number of gene therapy strategies under development. Next generation sequencing (NGS) of gene panels has proven a valuable diagnostic tool in IRD. We present the molecular findings of 677 individuals, residing in Denmark, with IRD and report 806 variants of which 187 are novel. We found that deletions and duplications spanning one or more exons can explain 3% of the cases, and thus copy number variation (CNV) analysis is important in molecular genetic diagnostics of IRD. Seven percent of the individuals have variants classified as pathogenic or likely-pathogenic in more than one gene. Possible Danish founder variants in EYS and RP1 are reported. A significant number of variants were classified as variants with unknown significance; reporting of these will hopefully contribute to the elucidation of the actual clinical consequence making the classification less troublesome in the future. In conclusion, this study underlines the relevance of performing targeted sequencing of IRD including CNV analysis as well as the importance of interaction with clinical diagnoses.
Highlights
The introduction of generation sequencing (NGS) has improved molecular genetic diagnosis of genetically heterogeneous conditions substantially
A genetic diagnosis is important to improve the genetic counselling of the families and for prognostic reasons and for identifying patients that might benefit from new candidate treatments such as gene therapy, where promising results are being reported in numerous clinical trials worldwide[4]
Targeted Next generation sequencing (NGS) analysis is a valuable method for molecular genetic diagnostics of Inherited retinal diseases (IRDs) as supported by several previous studies[16,17,18]
Summary
The introduction of generation sequencing (NGS) has improved molecular genetic diagnosis of genetically heterogeneous conditions substantially. This is true for inherited retinal diseases (IRDs) which are associated with sequence variations in more than 150 genes (https://sph.uth.edu/retnet/). Retinitis pigmentosa (RP) is the most frequent clinical diagnosis of the IRD specific diagnostic subgroups with a worldwide prevalence of 1:40002. Diagnoses include both syndromic and non-syndromic conditions. A genetic diagnosis is important to improve the genetic counselling of the families and for prognostic reasons and for identifying patients that might benefit from new candidate treatments such as gene therapy, where promising results are being reported in numerous clinical trials worldwide[4]. We report all variants that could be potentially disease causing; it is noteworthy that the number of rare variants per individual requires meticulous scrutiny combining several tools; and a close collaboration between clinical and laboratory medicine is mandatory
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