A Distinct Phenotype of Eyes Shut Homolog (EYS)-Retinitis Pigmentosa Is Associated With Variants Near the C-Terminus

Abstract

Purpose: Mutations in the eyes shut homolog (EYS) gene are a frequent cause of autosomal recessive retinitis pigmentosa (arRP). This study used multimodal retinal imaging to elucidate genotype-phenotype correlations in EYS-related RP (EYS-RP).

Design: Cross-sectional study.

Methods: Multimodal retinal imaging and electrophysiologic testing were assessed for 16 patients with genetic confirmation of EYS-RP.

Results: A total of 27 unique EYS variants were identified in 16 patients. Seven patients presented with an unusual crescent-shaped hyperautofluorescent (hyperAF) ring on fundus autofluorescence (FAF) imaging encompassing a large nasal-superior area of the posterior pole. Three patients had a typical circular or oval perifoveal hyperAF ring and 6 patients had no hyperAF ring. Spectral-domain (SD) and en face optical coherence tomography (OCT) showed preserved ellipsoid zone and retinal thickness spatially corresponding to areas within the hyperAF rings. Eleven patients presented with a rod-cone dystrophy on full-field electroretinogram (ffERG), 1 patient presented with cone-rod dystrophy, and 4 patients did not undergo ffERG testing. A significant spatial association was found between EYS variant position and FAF phenotype, with variants occurring at a nucleotide position greater than GRCh37 6:65300137 (c.5617C) being more associated with patients exhibiting hyperAF rings at presentation.

Conclusions: EYS-RP is a heterogeneous manifestation. Variants occurring in positions closer to the C-terminus of EYS are more common in patients presenting with hyperAF rings on FAF imaging.

Figure 1.. EYS-associated Retinitis Pigmentosa.

Digital color fundus photos of the right and left macula (top row) show attenuated arterioles, pale discs, and sparse intraretinal pigment migration (arrows) in a patient with EYS-RP (P8). Short wavelength FAF of both eyes (second row) reveals the typical phenotype of RP with a circular perifoveal hyperautofluorescent ring (arrows) and peripheral RPE atrophy. Note the ring is symmetric and round. High resolution SD-OCT imaging through the right (third row) and left (fourth row) fovea shows characteristic peripheral thinning of the outer retinal laminae and shortening of the ellipsoid zone line which is spared in the central macula. EYS, eyes shut homolog; RP, retinitis pigmentosa; RPE, retinal pigment epithelium; FAF, fundus autofluorescence.

Figure 2.. Heterogeneous phenotype of EYS-RP on FAF.

Short wavelength FAF imaging of each patient (30 degree field). Seven patients (P1–7) had atypical, larger crescent-shaped FAF rings. EYS, eyes shut homolog; RP, retinitis pigmentosa; FAF, fundus autofluorescence.

Figure 3.. Wide-field FAF imaging of an unusual EYS-RP phenotype with FAF ring boundaries appearing crescent-like.

Short wavelength FAF imaging of the right and left eyes of each patient exhibiting an atypical FAF ring phenotype (55 degree field). Note the varying levels of macular involvement amongst patients and the asymmetric presentation of P3. EYS, eyes shut homolog; RP, retinitis pigmentosa; FAF, fundus autofluorescence.

Figure 4.. En face OCT of EYS-RP patients.

Short wavelength FAF images (first column) aligned with retinal thickness heat maps (second column) and en face OCT at the level of the IS/OS junction (third column) in EYS-RP. EYS patients with a larger ring exhibited a smaller area of thinned retina and EZ loss. Preserved retinal thickness and spared EZ spatially corresponded to the shape of the ring. In patients with no ring (P13 and P16), retinal thickness corresponded most to the nerve fiber layer and greater EZ loss was noted. EYS, eyes shut homolog; RP, retinitis pigmentosa; FAF, fundus autofluorescence; IS/OS, inner segment/outer segment; EZ, ellipsoid zone.

Figure 5.. Schematic representation of EYS protein domains and the distribution of variants with respect to FAF phenotype.

Variants identified in the coding region are listed in red with the putative position of non-coding variants listed in black and indicated by black dotted lines. Patients in the crescent and typical ring groups harbored variants which clustered predominantly in the Laminin G domains toward the carboxy (−COOH) end of the protein. Patients that exhibited advanced disease (no ring) harbored variants which clustered predominantly in the amino (−NH₂) end of the protein amongst the epidermal growth factor (EGF) domains. EYS, eyes shut homolog; FAF, fundus autofluorescence.