Blue cone monochromacy with parafoveal hyperautofluorescent ring caused by a novel OPN1LW p.Ile109Asn variant

Blue Cone Monochromacy is a rare X-linked retinal disorder characterized by the selective loss of long-(L) and medium-(M) wavelength-sensitive cone function. While typically caused by large-scale genomic deletions or rearrangements within the OPN1LW/OPN1MW gene cluster, missense mutations are less common. Because blue cone monochromacy is often considered a stationary, congenital condition, sporadic cases lacking a family history can often be misidentified.

A 12-year-old boy presented with reduced visual acuity and a parafoveal hyperautofluorescent ring pattern on fundus autofluorescence and was initially referred for work-up of CRX-related maculopathy. However, electroretinography (ERG) revealed preserved S-cone and rod function with moderately reduced photopic responses. Genetic sequencing identified a novel, maternally inherited, hemizygous missense mutation in the gene encoding OPN1LW (c.326T > A; p.Ile109Asn). AlphaFold simulations demonstrated that the substitution disrupts the 11-cis-retinal binding pocket by altering the hydrogen bonding network near the critical Lys312 residue. This structural instability likely impairs the phototransduction cascade and delays chromophore clearance, contributing to localized foveal photoreceptor stress and the observed macular structural changes.

This report identifies a novel OPN1LW missense variant and provides a mechanistic basis for its pathogenicity through advanced structural modeling. Our findings demonstrate that blue cone monochromacy can present with atypical, progressive-appearing macular features, potentially mimicking Stargardt disease or other maculopathies. Furthermore, this case highlights the utility of in silico protein modeling in bridging the gap between variants and clinical phenotypes, expanding the known molecular spectrum of X-linked cone disorders.