The cone photoreceptor mosaic in aniridia: within-family phenotype-genotype discordance.

Purpose: Investigate in-vivo cone photoreceptor structure in familial aniridia caused by a deletion in the PAX6 gene to elucidate the complexity of between-individual variation in retinal phenotype. Design: Descriptive case-control study Participants: Eight persons with congenital aniridia (5 males; aged 40–66) from one family and 33 normal controls (14 males, aged 14–69 yrs), including seven unaffected family members (3 males; aged 14–53yrs). Methods: DNA was isolated from saliva samples and used in PCR to amplify and sequence exons and intron/exon junctions of the PAX6 gene. Fluorescent DNA sequencing was performed on both DNA strands. High-resolution retinal images were acquired with Heidelberg Spectralis (SD-OCT2) and Adaptive optics scanning light ophthalmoscopy (AOSLO). Cone density (CD; cones/mm2) and mosaic regularity were estimated along nasal-temporal meridians within the central 0–5° eccentricity. Horizontal SD-OCT line scans were segmented to analyze severity of foveal hypoplasia and measure retinal layer thicknesses. Main Outcomes and Measures: Within-family variability in macular retinal layer thicknesses, cone photoreceptor density and mosaic regularity in aniridia compared with normal controls. Results: DNA sequencing revealed a known PAX6 mutation (IV2-2delA). Those with aniridia had variable iris phenotype ranging from almost normal appearance to no iris. Four with aniridia had FH grade 2, two had grade 3 and one had grade 4. Visual acuity ranged from 0.20–0.86 logMAR. AOSLO images were acquired of five family members with aniridia. Foveal CD varied between 19899 and 55128 cones/mm2 with overlap between the foveal hypoplasia grades. CD was ≥3 SD below the normal mean within 0.5°, ≥2 SD below the normal mean at 0.5°–4°, and >1SD below the normal mean at 5° retinal eccentricity. Conclusions: The results show considerable variability in foveal development within a family carrying the same PAX6 mutation. This, together with the structural and functional variability within each grade of foveal hypoplasia, underlines the importance of advancing knowledge about retinal cellular phenotype in aniridia.