Association of CRX genotypes and retinal phenotypes confounded by variable expressivity and electronegative electroretinogram.

Importance A framework for understanding the phenotypic features ofCRXretinopathy was established. Background To perform a phenotype-genotype correlation analysis in two groups of patients with heterozygous mutations in distinct locations of theCRXgene, encoding the cone-rod homeobox. Design Multicentre retrospective study. Participants Twenty-one Japanese patients from 14 families with a heterozygousCRXmutation. Methods Retrospective data analysis. Main Outcome Measures Clinical records onCRXmutation, symptoms, best-corrected visual acuity (BCVA), visual field, fundus photography, fundus auto-fluorescence, optical coherence tomography and electroretinograms (ERGs). Results Six differentCRXheterozygous mutations were identified in the subjects. Twelve patients from 9 families shared the p.R41W mutation and 1 patient had the p.R43C mutation, both of which affect the homeobox domain ofCRX. These patients often displayed adult-onset retinal dystrophy with macular degeneration. In contrast, five patients with downstream mutations (p.S204fs, p.S213fs, p.G243X and p.L299F) displayed retinal degeneration or macular degeneration with bone-spicule pigmentation. Three asymptomatic carriers with different mutations (p.R41W, p.S213fs and p.G243X) were present in both groups. Nearly all patients and carriers had an electronegative ERG in response to a bright flash under dark adaptation. There was no cross-sectional association between patients' age and BCVA, despite progressive decline in BCVA. Conclusions and Relevance Heterozygous mutations within or downstream of the homeobox domain inCRXrelate to the difference associated retinal phenotypes, which was confounded by variable expressivity and electronegative ERGs.CRXmutations should be considered in patients with an electronegative ERG with minimal or no macular changes.