GUCY2D-Related Retinal Dystrophy with Autosomal Dominant Inheritance-A Multicenter Case Series and Review of Reported Data.

Jonas Neubauer,M Dominik Fischer,Peter Charbel Issa,Johannes Birtel,Leo Hahn,Camiel J F Boon

doi:10.3390/genes13020313

Abstract

To report the clinical phenotype and associated genotype of a European patient cohort with GUCY2D-related autosomal-dominant (AD) cone–/cone–rod dystrophy (COD/CORD), we retrospectively analyzed 25 patients (17 female, range 12–68) with GUCY2D-related AD-COD/CORD from three major academic centers in Europe and reviewed the previously published data of 148 patients (visual acuity (VA), foveal thickness, age of first symptoms, and genetic variant). Considering all the patients, the onset of first symptoms was reported at a median age of 7 years (interquartile range 5–19 years, n = 78), and mainly consisted of reduced VA, photophobia and color vision abnormality. The disease showed a high degree of inter-eye symmetry in terms of VA (n = 165, Spearman’s ρ = 0.85, p < 0.0001) and foveal thickness (Spearman’s ρ = 0.96, n = 38, p < 0.0001). Disease progression was assessed by plotting VA as a function of age (n = 170). A linear best-fit analysis suggested a loss of 0.17 logMAR per decade (p < 0.0001). We analyzed the largest cohort described so far (n = 173), and found that the most common mutations were p.(Arg838Cys) and p.(Arg838His). Furthermore, the majority of patients suffered severe vision loss in adulthood, highlighting a window of opportunity for potential intervention. The emerging patterns revealed by this study may aid in designing prospective natural history studies to further define endpoints for future interventional trials.

Highlights

Inherited retinal diseases (IRD) are a group of heterogeneous disorders caused by mutations in over 250 different genes that are important for retinal function [1]
25 patients (17 female) with AD COD/CORD associated with mutations in GUCY2D were included
We found it most appropriate to keep this patient in our analysis as a patient with autosomal dominant COD/CORD caused by the c.2516C>G, p.(Thr839Arg) variant

Summary

Introduction

Inherited retinal diseases (IRD) are a group of heterogeneous disorders caused by mutations in over 250 different genes that are important for retinal function [1]. A subgroup of these are autosomal-dominant (AD) cone–/cone–rod dystrophies (COD/CORD), which primarily affect cones, while rods may degenerate later and to a varying extent [2]. Subtle RPE changes may be observed in the early phase of the disease, which can later progress to bull’s eye maculopathy and, to central atrophy [4,5]. Its gene product is retinal guanylate cyclase 2D (RetGC-1), which is crucial in the phototransduction process of cones and rods. The RetGC-1 protein plays a pivotal role in restoring the original depolarized (dark-adapted) state of photoreceptors through the production of cGMP, thereby indirectly opening cGMP-dependent ion channels, which, in turn, leads to depolarization of the photoreceptors

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