Abstract
Retinitis pigmentosa (RP) is the most common inherited retinal disease. It is a clinically and genetically heterogeneous disorder, which is why it is particularly challenging to diagnose. The aim of this study was to establish a targeted next-generation sequencing (NGS) approach for the comprehensive, rapid, and cost-effective clinical molecular diagnosis of RP. A specific hereditary eye disease enrichment panel (HEDEP) based on exome capture technology was used to collect the protein coding regions of 371 targeted hereditary eye disease genes, followed by high-throughput sequencing on the Illumina HiSeq2000 platform. From a cohort of 34 Chinese RP families, 13 families were successfully diagnosed; thus, the method achieves a diagnostic rate of approximately 40%. Of 16 pathogenic mutations identified, 11 were novel. Our study demonstrates that targeted capture sequencing offers a rapid and effective method for the molecular diagnosis of RP, which helps to provide a more accurate clinical diagnosis and paves the way for genetic counseling, family planning, and future gene-targeted treatment.
Highlights
Retinitis pigmentosa (RP) is the most frequent subtype of inherited retinal disease and it is a clinically and genetically highly heterogeneous disorder [1]
The generated sequence covered an average of 99.2% of the targeted bases with a variant calling accuracy of more than 99%, which is sufficient to pass the thresholds for calling SNPs and short insertions or deletions
Targeted exon sequencing approaches, which focus on a panel of known candidate genes with deep coverage, allow for the unbiased and accurate identification of point mutations and small indels, and of large exonic deletions and insertions
Summary
Retinitis pigmentosa (RP) is the most frequent subtype of inherited retinal disease and it is a clinically and genetically highly heterogeneous disorder [1]. RP affects approximately 1 in 3,500 individuals worldwide [2], and data from the Beijing Eye Institute suggest that its prevalence may be even higher in China (approximately 1 in 1,000) [3]. Typical symptoms of RP include night blindness, followed by decreasing visual fields leading to tunnel vision, and eventually blindness. Clinical hallmarks include bone-spicule deposits, attenuated retinal blood vessels, optic disc pallor, visual field loss, and abnormal, diminished, or non-recordable electroretinographic responses. 74 genes have been associated with non-syndromic RP (RetNet; http://www.sph.uth.tmc.edu/Retnet/), which makes the dependable and efficient clinical molecular diagnosis of RP patients challenging.
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