Variants at codon 838 in the GUCY2D gene result in different phenotypes of cone rod dystrophy

The GUCY2D gene encodes the photoreceptor guanylate cyclase (GC-E) and different pathogenic variants can lead to Leber congenital amaurosis (LCA) or cone-rod dystrophy (CRD). In this study, we describe three unrelated families who carried different mutations at codon 838 of the GUCY2D gene, and presented different phenotypes of retinal degeneration.

Family and personal histories were collected, and the patients underwent best corrected visual acuity (BCVA), fundus photography (FP), electroretinography (ERG), optical coherence tomography (OCT) and fundus autofluorescence (FAF). Venous blood was drawn from patients and family members, and genomic DNA was extracted. Next-generation sequencing of known ocular genes was applied to the proband to find pathogenic variants. Polymerase chain reaction (PCR) and Sanger sequencing were conducted for validation and segregation.

Six patients from three unrelated families were enrolled. All the patients manifested decreased vision, photophobia and myopia from childhood. ERG recordings demonstrated a significant reduction in cone responses for all patients, while rod responses ranged widely from normal to moderately reduced. All patients were diagnosed with CRD, but the disease severity and progression rates in the three families were significantly different. Three pathogenic variants in the GUCY2D gene (c.2512 C > T (p.R838C), c.2512 C > A (p.R838S) and c.2513 G > A (p.R838H)) were identified.

We presented the phenotypes of three Chinese adCRD families carrying different variants at codon 838 of the GUCY2D gene. The R838S variant is a novel genotype associated with GUCY2D-CRD. The R838H variant can cause severe retinal features. Our findings enhance the understanding of GUCY2D phenotypic diversity.