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.