Clinical and genetic characterization of REEP6-associated retinopathy in a Japanese cohort.

PURPOSE: To characterize the clinical and genetic features of REEP6-associated retinopathy in 8 Japanese patients from 7 families STUDY DESIGN: Retrospective, multicenter cohort study METHODS: Biallelic REEP6 variants were identified by use of whole-exome sequencing in patients with inherited retinal dystrophy (IRD). Comprehensive ophthalmic assessments were performed in all the patients.

RESULTS: Among a nationwide cohort of 2011 patients with IRD, 8 patients from 7 families were found to carry biallelic REEP6 variants. Four distinct variants were identified: c.223G>A, p.Glu75Lys; c.268G>C, p.Val90Leu; c.280_281del, p.Leu94ValfsTer86 (novel frameshift), and c.598+1G>A. Five families (Families 1-5) carried the compound heterozygous p.Val90Leu and c.598+1G>A variants. The other two had either homozygous c.598+1G>A (Family 6) or compound heterozygous p.Glu75Lys/p.Leu94ValfsTer86 (Family 7). In Families 1-5, the patients exhibited relatively mild phenotypes with limited to peripheral retinal degeneration in the younger patients and gradual posterior pole involvement in the older patients. Optical coherence tomography revealed well-preserved outer retinal layers at the macula, and good visual acuity was maintained even in some of the older patients. In contrast, the 2 patients in Families 6 and 7 exhibited more severe phenotypes, including macular atrophy and visual acuity decline.

CONCLUSIONS: The combination of p.Val90Leu and c.598+1G>A variants was associated with a milder phenotype, supporting the hypothesis that p.Val90Leu is a hypomorphic variant. These findings expand the clinical and genetic spectra of REEP6-associated retinopathy, particularly among East Asian populations.