27-year follow-up of Japanese siblings with juvenile cone rod dystrophy 13 due to a novel RPGRIP1 gene mutation

Abstract

Purpose : Since inherited retinal degenerative diseases (IRDs) presents genetic heterogeneity, it is difficult to presume the genotype from its phenotype with a few exceptions. In this report, we identified a novel pathogenic variant in RPGRIP1 gene, which was reported LCA 6 or cone rod dystrophy 13 (CORD13), in Japanese siblings who had been clinically diagnosed rod monochromacy (RMCH).

Methods : We conducted whole exome sequencing (WES) on Japanese siblings who gave a written consent for genetic testing. Both participants underwent complete ophthalmic examinations. For sequencing, Illumina's Hiseq 2500 Platform was used. Sequence reads were aligned to the reference human genome (UCSC hg19). After cleaning and filtering the sequence data, we checked variants of the known causative genes of IRDs listed in RetNet^TM database.

Results : The siblings had been followed in our clinic since 1989. Unfortunately, clinical records until 1992 were not left. According to interview, their parents were not consanguineous, and no other patient was in their family. No general medical history about them should be noted. His mother was aware of their nystagmus immediately after birth. They had been complained photophobia. Elder brother was 38-year-old. His BCVA was 0.1 in the right and 0.1 in the left in 1992. Color sensing test was revealed RM pattern. Bright flash ERG was subnormal pattern, and 30Hz flicker ERG was non recordable. He was diagnosed as RMCH clinically. His BCVA was 0.09 in the right and 0.09 in the left in 2019. Younger sister was 34-year-old. Her BCVA was 0.06 in the right and 0.05 in the left in 1992. She was also diagnosed as RMCH. Her BCVA was 0.02 in the right and 0.03 in the left in 2019. WES revealed that both patients had a novel rare homozygote variant (NM020366: exon15: c.G2294A and c.C2295A: p.C765X) in the RPGRIP1 gene. This variant made a premature stop codon. No other candidate variant for IRDs, including RMCH, was detected in them. We thought this variant was pathogenic, because several nonsense variants downstream of the detected variant have been reported as pathogenic mutations. Finally, we had made a genetic diagnosis for them as CORD13.

Conclusions : With WES, we detected a novel pathogenic mutation in RPGRIP1 gene. Long-term follow-up data with genetic diagnosis provides important information for prognosis prediction and/or genetic counseling for IRDs.

This is a 2020 ARVO Annual Meeting abstract.