Phenotypic variability of a dominant CRX mutation and molecular insights into pathogenesis

Mutations in the cone-rod homeobox (CRX) gene cause dominantly inherited retinopathies with striking phenotypic variability. We define the clinical spectrum and molecular mechanism of a Class III CRX frameshift variant (c.590del, p.(Pro197Argfs*22); CRX^P197Rfs) segregating in a four-generation family.

Six family members underwent genetic testing by a retinal dystrophy panel with Sanger confirmation. Carriers received longitudinal phenotyping, including visual acuity, fundus autofluorescence, optical coherence tomography (OCT), and full-field electroretinography (ffERG). Variant function was assessed by rhodopsin-promoter reporter assays in HEK293 cells and Crx^-/- mouse retinal explants.

Three carriers shared the identical variant yet showed cone-rod dystrophy in variable severity and adult-onset ages. The proband developed progressive central vision loss, nyctalopia, outer-retinal atrophy, and reduced ffERG responses. Two carriers remained asymptomatic with preserved acuity and normal ffERG, exhibiting only mild outer nuclear layer thinning and abnormal autofluorescence. CRX^P197Rfs lacked transactivation activity and suppressed wild-type CRX function in a dose-dependent manner.

CRX^P197Rfs is a dominant-negative allele that produces cone-rod dystrophy with variable intrafamilial phenotypes. These findings caution against genotype-based prognostication and support mutant-allele knockdown with gene augmentation as therapeutic strategies.