Genotypic and Phenotypic Characterization of a Cohort of Patients Affected by Rod Cyclic Nucleotide Channel-Associated Retinitis Pigmentosa

Abstract

<b><i>Introduction:</i></b> Retinitis pigmentosa (RP), a heterogeneous inherited retinal disorder causing gradual vision loss, affects over 1 million people worldwide. Pathogenic variants in <i>CNGA1</i> and <i>CNGB1</i> genes, respectively, accounting for 1% and 4% of cases, impact the cyclic nucleotide-gated channel in rod photoreceptor cells. The aim of this study was to describe and compare genotypic and clinical characteristics of a cohort of patients with <i>CNGA1</i>- or <i>CNGB1</i>-related RP and to explore potential genotype-phenotype correlations. <b><i>Methods:</i></b> The following data from patients with <i>CNGA1</i>- or <i>CNGB1</i>-related RP, followed in five Italian inherited retinal degenerations services, were retrospectively collected: genetic variants in <i>CNGA1</i> and <i>CNGB1</i>, best-corrected visual acuity (BCVA), ellipsoid zone (EZ) width, fundus photographs, and short-wavelength fundus autofluorescence (SW-AF) images. Comparisons and correlation analyses were performed by first dividing the cohort in two groups according to the gene responsible for the disease (<i>CNGA1</i> and <i>CNGB1</i> groups). In parallel, the whole cohort of RP patients was divided into two other groups, according to the expected impact of the variants at protein level (low and high group). <b><i>Results:</i></b> In total, 29 patients were recruited, 11 with <i>CNGA1</i>- and 18 with <i>CNGB1</i>-related RP. In both CNGA1 and CNGB1, 5 novel variants in <i>CNGA1</i> and 5 in <i>CNGB1</i> were found. BCVA was comparable between <i>CNGA1</i> and <i>CNGB1</i> groups, as well as between low and high groups. <i>CNGA1</i> group had a larger mean EZ width compared to <i>CNGB1</i> group, albeit not statistically significant, while EZ width did not differ between low and high groups A statistically significant correlation between EZ width and BCVA as well as between EZ width and age were observed in the whole cohort of RP patients. Fundus photographs of all patients in the cohort showed classic RP pattern, and in SW-AF images an hyperautofluorescent ring was observed in 14/21 patients. <b><i>Conclusion:</i></b> Rod CNG channel-associated RP was demonstrated to be a slowly progressive disease in both <i>CNGA1</i>- and <i>CNGB1</i>-related forms, making it an ideal candidate for gene augmentation therapies.