Intrafamilial phenotypic variability in CRX-associated retinopathy due to a frameshift variant (c.661del).

PURPOSE: We report the detailed ophthalmological evaluation of two affected members of the same family (mother and son) carrying the heterozygous pathogenic CRX frameshift variant (NM_000554.6:c.661del; p. Tyr221Thrfs *9), both presenting with photophobia and photopsia but exhibiting markedly different clinical manifestations.

METHODS

Both individuals underwent comprehensive ophthalmological assessment, including best-corrected visual acuity, multimodal retinal imaging (ultra-widefield fundus autofluorescence, ultra-widefield pseudocolor imaging, and spectral-domain optical coherence tomography, full-field electroretinography, kinetic perimetry, full-field stimulus threshold testing (FST), and chromatic pupillometry. The CRX variant was identified by next-generation sequencing and confirmed by Sanger sequencing in the mother.

RESULTS

The 45-year-old son was diagnosed with cone dystrophy (COD), characterized by progressive central visual loss, cone dysfunction on electroretinography, and a distinctive bifocal retinal degeneration involving both the macula and nasal retina. In contrast, his 71-year-old mother exhibited a milder macular-confined phenotype consistent with macular dystrophy (MD), with normal full-field electroretinography and structural abnormalities limited to the macula on optical coherence tomography.

CONCLUSIONS

The marked differences in functional and structural findings support variable intrafamilial expressivity. To our knowledge, this is the first report associating the c.661del (p. Tyr221Thrfs *9) variant with cone dystrophy presenting as bifocal retinal degeneration, thereby expanding both the phenotypic spectrum associated with this variant and the mutational spectrum of CRX-associated bifocal retinal degeneration.