Abstract
Retinitis pigmentosa (RP) is a genetically highly heterogeneous retinal disease and one of the leading causes of blindness in the world. Next-generation sequencing technology has enormous potential for determining the genetic etiology of RP. We sought to identify the underlying genetic defect in a 35-year-old male from an autosomal-dominant RP family with 14 affected individuals. By capturing next-generation sequencing (CNGS) of 144 genes associated with retinal diseases, we identified eight novel DNA variants; however, none of them cosegregated for all the members of the family. Further analysis of the CNGS data led to identification of a recurrent missense mutation (c.403C > T, p.R135W) in the rhodopsin (RHO) gene, which cosegregated with all affected individuals in the family and was not observed in any of the unaffected family members. The p.R135W mutation has a reference single nucleotide polymorphism (SNP) ID (rs104893775), and it appears to be responsible for the disease in this large family. This study highlights the importance of examining NGS data with reference SNP IDs. Thus, our study is important for data analysis of NGS-based clinical genetic diagnoses.
Highlights
Previous study provided support for using NGS as an effective approach to distinguishing cone-rod dystrophy and Stargardt disease, two inherited retinopathies with overlapping clinical symptoms[7]
Because it has been reported that mutations in the RHO gene account for 7.7% to 40% of all adRP cases in different populations[6,15,16], we investigated whether the mutation in the family of study was located in the area of missing sequence coverage in the RHO gene
Because the pathogenic mutations for autosomal-recessive disorders may be recorded in the dbSNP database, DNA variants with SNP IDs could be assigned as candidate mutations[26,27]
Summary
Previous study provided support for using NGS as an effective approach to distinguishing cone-rod dystrophy and Stargardt disease, two inherited retinopathies with overlapping clinical symptoms[7]. Patients and unaffected individuals from a five-generation family with fourteen individuals diagnosed with RP were recruited. We sought to identify the underlying genetic defect in this family by capturing next-generation sequencing (CNGS) and Sanger sequencing. These approaches led to identification of eight novel DNA variants, but the variants did not cosegregate with all affected individuals in the family, indicating none of them was the disease-causing mutation. Re-analysis of the data was necessary because the disease-causing gene may already be identified or be outside of the panel of the captured genes. We observed a recurrent mutation (p.R135W) in the rhodopsin (RHO) gene with reference SNP ID (rs104893775, http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref. cgi?rs= 104893775)
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