Abstract
Purpose :
The open-reading frame 15 (ORF15) of RPGR is a major area for mutations which lead to X-linked retinitis pigmentosa (RP) and accounts for approximately half of X-linked RP cases. However, mutations in the ORF15 are not easy to be identified through capture-based next-generation sequencing (NGS) method due to low capture efficiency within the highly repetitive, purine-rich regions in this area for about 1kb. To enhance the detection rate of genetic testing in clinical practice, we evaluate the performance for identifying mutations in ORF15 region through whole genome sequencing (WGS) method.
Methods :
A total of 10 samples from 5 unrelated families were tested with WGS. These samples were selected from pedigrees showed a pattern consistent with X-linked or X-linked dominant RP but negative finding for initially capture-based NGS retinal dystrophy panel which included 212 disease-related genes. ORF15 mutations identified via WGS were later confirmed by Sanger sequencing.
Results :
Among our patients examined, one novel frameshift variant in the RPGR exon ORF15 has been identified in two unrelated probands and their family members. Proband 1 was a 9 year-old male who carried a hemizygous pathogenic mutation (c.[2602_2617dup];[0]). His younger sister was also diagnosed with early-onset retinal degeneration with the same heterozygous mutation (c.[2602_2617dup];[2602_2617=]). Proband 2, was a 40 year-old female who carried a heterozygous mutation (c.[2602_2617dup];[2602_2617=]). Her younger brother carried the same mutation as hemizygous pattern (c.[2602_2617dup];[0]).
Conclusions :
Here we report a novel pathogenic variant, c.2602_2617dup, in the RPGR exon ORF15 which has been identified through WGS. The mutation could lead to disease phenotype in both male and female patients, suggesting the X-linked dominant inheritance pattern. This finding also indicates that WGS can be a helpful tool for detecting variants in the highly repetitive region of RPGR exon ORF15, which may be important for bridging gene therapy in the near future.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.