Genetic epidemiology of inherited retinal diseases in a large patient cohort followed at a single center in Italy

Abstract

Inherited retinal diseases (IRDs) are the leading cause of vision loss in the working-age population. We performed a retrospective epidemiological study to determine the genetic basis of IRDs in a large Italian cohort (n = 2790) followed at a single referral center. We provided, mainly by next generation sequencing, potentially conclusive molecular diagnosis for 2036 patients (from 1683 unrelated families). We identified a total of 1319 causative sequence variations in 132 genes, including 353 novel variants, and 866 possibly actionable genotypes for therapeutic approaches. ABCA4 was the most frequently mutated gene (n = 535; 26.3% of solved cases), followed by USH2A (n = 228; 11.2%) and RPGR (n = 102; 5.01%). The other 129 genes had a lower contribution to IRD pathogenesis (e.g. CHM 3.5%, RHO 3.5%; MYO7A 3.4%; CRB1 2.7%; RPE65 2%, RP1 1.8%; GUCY2D 1.7%). Seventy-eight genes were mutated in five patients or less. Mitochondrial DNA variants were responsible for 2.1% of cases. Our analysis confirms the complex genetic etiology of IRDs and reveals the high prevalence of ABCA4 and USH2A mutations. This study also uncovers genetic associations with a spectrum of clinical subgroups and highlights a valuable number of cases potentially eligible for clinical trials and, ultimately, for molecular therapies.

A Description of the Yield of Genetic Reinvestigation in Patients with Inherited Retinal Dystrophies and Previous Inconclusive Genetic Testing

“…Our secondmost common genes were RPGR and CEP290, which were found in 6% of the patients, respectively. RGPR is also among the most prevalent genes in other studies; fourth-most common in the GRID dataset (3.4%) [13], in USA and Canada it was the third-most common gene (10% and 4%) [36], the fourth-most common in Brazil (5%) [37], fifth-most common in Taiwan (5%) [38], and in the Italian cohort, it was the third-most common gene (5%) [39]. CEP 290, on the other hand, is only represented to the same extent in the Brazilian cohort (5.5%) [37], while it is less common in the other cohorts (1-3%) [13,36,38,39].…”

“…RGPR is also among the most prevalent genes in other studies; fourth-most common in the GRID dataset (3.4%) [13], in USA and Canada it was the third-most common gene (10% and 4%) [36], the fourth-most common in Brazil (5%) [37], fifth-most common in Taiwan (5%) [38], and in the Italian cohort, it was the third-most common gene (5%) [39]. CEP 290, on the other hand, is only represented to the same extent in the Brazilian cohort (5.5%) [37], while it is less common in the other cohorts (1-3%) [13,36,38,39]. Another difference is that USH2A is quite common in the other studies, being the second-most prevalent gene in the GRID dataset (15%) [13] as well as in the Italian (11%) [39] and the Canadian (6%) [36] cohorts, the third-most prevalent gene in Taiwan and Brazil (10% and 5%, respectively) [37,38], and found in 3% of American IRD patients [36], while it was found in only two of our 182 patients (1.1%) with a verified genotype.…”

“…When it comes to the prevalence of different causative genes in this Swedish cohort, which to our knowledge is the first larger cohort investigated concerning the genetic spectrum in Sweden, the ABCA4 gene was the most common gene, encountered in 16.5% of the patients. This is in line with both an international estimate by Schneider et.al., 2022 called the Global Retinal Inherited Disease (GRID) dataset [13], and with reports from separate countries, although the absolute percentage varies slightly: GRID 25%, USA 14% [36], Canada 20% [36], Brazil 21% [37], Taiwan 15% [38], and Italy 26% [39]. Our secondmost common genes were RPGR and CEP290, which were found in 6% of the patients, respectively.…”

“…CEP 290, on the other hand, is only represented to the same extent in the Brazilian cohort (5.5%) [37], while it is less common in the other cohorts (1-3%) [13,36,38,39]. Another difference is that USH2A is quite common in the other studies, being the second-most prevalent gene in the GRID dataset (15%) [13] as well as in the Italian (11%) [39] and the Canadian (6%) [36] cohorts, the third-most prevalent gene in Taiwan and Brazil (10% and 5%, respectively) [37,38], and found in 3% of American IRD patients [36], while it was found in only two of our 182 patients (1.1%) with a verified genotype. It is well known that genes have different prevalences in various countries and geographic areas, but most of the difference concerning the USH2A gene in our study can be explained by the fact that the patients with Usher syndrome type 2A are referred to us at an older age (mean age 39 at genotypic diagnosis in our registry) than the investigated group, since their visual decline becomes evident somewhat later in life.…”

Discovery of Nonretinoid Inhibitors of CRBP1: Structural and Dynamic Insights for Ligand-Binding Mechanisms

“…31 Additionally, mutations in the RBP1 gene have not been reported to cause human retinal disorders. 33 Thus, the physiological function of CRBP1 preordains this protein as a pharmacological target for controlling the flux of retinoids in the eye without causing serious ocular side effects.…”