Shared mutations in NR2E3 in enhanced S-cone syndrome, Goldmann-Favre syndrome, and many cases of clumped pigmentary retinal degeneration

Objectives: To determine if enhanced s-cone syndrome (ESCS), Goldmann-Favre syndrome (GFS), and clumped pigmentary retinal degeneration (CPRD) are caused by mutations in the NR2E3 gene and to characterize the clinical findings in patients with NR2E3 mutations. Patients: One patient with ESCS, one with GFS, and 20 with CPRD. Methods: The coding regions of the NR2E3 and NRL genes and part of the THRB1 coding region were scanned for mutations using single-strand conformation and direct sequencing methods. We evaluated visual acuity, refractive error, visual fields, fundi, final dark-adaptation thresholds, and electroretinograms (ERGs). Results: The patients with ESCS and GFS and 9 of the 20 unrelated patients with CPRD had mutations in the NR2E3 gene. Six mutations were found in these 11 patients, including 2 novel mutations: the missense mutation Ala256Glu and the frameshift mutation Pro276del17 (the first obviously null allele reported). Three patients were mutant homozygotes, and 8 had 2 mutations. All but one of the mutations in the patients with ESCS and GFS were also found in patients with CPRD. All NR2E3 cases were hyperopes and had retinal vascular attenuation and reduced and delayed full-field ERGS. Clumped pigment deposits were recognized in the patients with ESCS and GFS. The CPRD patients without NR2E3 mutations had no detected mutations in NRL or THRB1. Conclusions: We found that ESCS, GFS, and CPRD can all have the same genetic basis. Clinical Relevance: The combination of night blindness, hyperopia, and clumped retinal pigment deposits should raise the suspicion that a patient has NR2E3 disease.