Novel GUCY2D variant (E843Q) at mutation hotspot associated with macular dystrophy in Japanese patient

BACKGROUND: The GUCY2D (guanylate cyclase 2D) gene encodes a photoreceptor guanylate cyclase (GC-E) that is predominantly expressed in the cone outer segments. Mutations in the GUCY2D lead to severe retinal disorders such as autosomal dominant cone-rod dystrophy (adCRD) and autosomal recessive Leber congenital amaurosis type 1. The purpose of this study was to determine the phenotype of a Japanese patient with a probably pathogenic GUCY2D variant. METHODS: Detailed ophthalmic examinations were performed, and whole exome sequencing was performed on the DNA obtained from the patient. The variants identified by exome sequencing and targeted analysis were further confirmed by direct sequencing. RESULTS: A 47-years-old man had atrophic and pigmentary changes in the macula of both eyes. The amplitudes and implicit times of the full-field electroretinograms (ERGs) were within normal limits, however the densities of the multifocal ERGs in the central area were reduced in both eyes. Whole exome sequencing identified heterozygous variant c.2527G>C, p.Glu843Gln in the GUCY2D gene within the mutation hot spot for adCRD. The allelic frequencies of this variant was extremely low and according to ACMG standards and guidelines, the variants were classified as likely pathogenic. CONCLUSIONS: This is the first report on the findings in a patient with a heterozygous variant, c.2527G>C, p.Glu843Gln in the GUCY2D, presenting with mild macular dystrophy without a general reduction of cone function. Our findings expand the spectrum of the clinical phenotypes of GUCY2D-adCRD and help identify the morphological and functional changes caused by defects of dimerization of GC-E in the phototransduction cascade.