RGR gene mutation causative of peripapillary choroidal atrophy

Abstract

Purpose: To find genetic mutation causative of peripapillary atrophy with slow progression

Methods: A 50 yr old patient with peripapillary atrophy was examined at the WVU Eye Institute. Family history includes his father, who at age 80 had widespread choroidal atrophy and an aunt with more extensive peripapillary atrophy threatening the fovea. His cousin presented with similar peripapillary atrophy. Visual acuity and ERG ranged from normal in the proband, to severe visual impairment with both scotopic and photopic amplitude reduction in the older generation. Both patients were evaluated for mutation in the genes, CHM and PRPH2, by Sanger sequencing, and then further evaluated for mutations in a panel of genes responsible for retinal dystrophies using microdroplet PCR (RainDance, Inc) and NGS sequencing (Illumina). Candidate mutations were further evaluated in additional affected and unaffected family members by Sanger sequencing.

Results: No mutation was identified in the CHM and PRPH2 genes. With a newly developed assay that targeted 3071 amplicons from 2078 exons of 184 genes involved in retinal function and/or retinal development, a candidate mutation was found in both affected male patients. This candidate mutation was in the RGR gene and had been reported previously with an apparently dominant inheritance. The mutation was a duplicated G after the G at position 824 (c.824dupG, p.I276N*77; HGMD:CI993291) which changed the reading frame at the last exon of RGR gene. We further confirmed segregation in two additional affected female patients in this family and found an unaffected female family member to be mutation-negative.

Conclusions: Our analyses provide genetic evidence and molecular confirmation to conclude the causative mutation in the RGR gene for the phenotype in this family.

Keywords: 452 choroid • 507 electrophysiology: clinical • 537 gene screening