Retinal structure variation in congenital aniridia: within family phenotype-genotype discordance

Abstract

Purpose : Congenital aniridia is an autosomal dominant disorder affecting retinal development and foveal hypoplasia. We investigated photoreceptor structure in a family with aniridia caused by a deletion in the PAX6 gene.

Methods : Six persons (3 males) with congenital aniridia, aged 24–66yrs, and 10 age-matched normal controls (4 males) were included in the study. DNA was isolated from saliva samples, and used in the polymerase chain reaction (PCR) to amplify and sequence the exons and intron/exon junctions of the PAX6 gene. The PCR primers and conditions were those described previously (Human Genome Variation (2016) 3:15052). Fluorescent DNA sequencing was performed on both DNA strands. Visual acuity and ocular media opacities were evaluated. High-resolution retinal images were acquired with Heidelberg Spectralis SD-OCT2 and adaptive optics scanning light ophthalmoscopy (AOSLO). Cones were identified and cone density (CD; cones/mm²) was estimated along nasal-temporal meridians within the central 0–5°eccentricity. Horizontal SD-OCT line scans were segmented to analyze severity of foveal hypoplasia (FH, normal to complete: 0–4).

Results : DNA sequencing revealed a deletion of the -2 nucleotide in intron 2 (IV2-2delA), disrupting the consensus 3’ splice site for exon 3; a known aniridia-causing mutation. Those with aniridia had severe iris hypoplasia. Visual acuity ranged from 0.22–0.86 logMAR. AOSLO images were obtained of four (3 males) family members with aniridia, two pseudophakic and two with lens opacities (LOCSIII: N2-C1-P1, N1-C3-P1). FH grade were obtained for all six. Three with aniridia had FH grade 2 (all males) and three had grade 3 (all females), two of the females also had optic nerve hypoplasia and nystagmus. Foveal CD in aniridia ranged from 17831–53683 cones/mm² with overlap between FH grade 2 and 3. No relationship between CD and visual acuity was observed. CD was significantly lower in aniridia, with CD >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° eccentricity.

Conclusions : The results show considerable difference in structural phenotype in family members with aniridia and the same genetic mutation; females being more affected than males. The lack of correlation between CD and visual acuity suggests that visual function in aniridia may be related to altered numbers of post-receptoral neurons and associated circuitry.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.