To describe the natural history, genetic landscape, and phenotypic spectrum of Eyes shut homolog (EYS)-associated retinal degeneration (EYS-RD). Retrospective, single-center cohort study complemented by a cross-sectional examination. Patients with biallelic EYS variants were recruited at an inherited RD referral center in Portugal. Every patient underwent a cross-sectional examination comprising a comprehensive ophthalmic examination including best-corrected visual acuity (BCVA), dilated slit-lamp anterior segment, and fundus biomicroscopy; ultrawide-field color fundus photography and fundus autofluorescence imaging; and spectral domain-OCT. In the setting of a retinitis pigmentosa (RP) diagnosis, every patient was classified as typical or atypical RP according to imaging criteria. Baseline demographics, age at onset of symptoms, family history, history of consanguinity, symptoms, age at diagnosis, BCVA at baseline and throughout follow-up, and EYS variants were collected from each individual patient file. Clinical/demographic, genetic, multimodal imaging data, and BCVA variation were compared between typical and atypical RP. Additionally, BCVA variation during follow-up was used as an endpoint to describe EYS-RD natural history. Fifty-eight patients (59% men; mean age 52 ± 14 years) from 48 White families of Portuguese ancestry were included. Twenty distinct EYS variants were identified, 8 of which are novel. In 32.8% of patients, onset of symptoms was in early adulthood (21-30 years). A clinical diagnosis of RP was established in 57 patients and cone-rod dystrophy in 1 patient. Regarding RP, 75.0% of the patients were graded as typical and 25.0% as atypical. Atypical EYS-RP commonly presents with inferior crescent-shaped macular atrophy with superior midperipheral sparing. In EYS-RD, a negative correlation was found between age and BCVA (r = -0.50; P < 0.001), with an average loss of 1.45 letters per year. When stratifying for RP phenotype, lower average loss of letters per year (P < 0.001), higher BCVA (P < 0.001), and larger ellipsoid zone widths (P < 0.001) were found in atypical RP. This study expands the genetic spectrum of EYS-RD by reporting 8 novel variants. A high frequency of atypical phenotypes was identified. These patients have better BCVA and larger ellipsoidal zone widths, thus presenting an overall better prognosis. Proprietary or commercial disclosure may be found after the references.

This study aims to characterize the clinical spectrum and genetic landscape of IRDs in Portugal. Multicentre, cross-sectional, cohort study comprising consecutive patients with a clinical diagnosis of IRD and available genetic results, enroled in the IRD-PT registry (retina.com.pt). Among the 1369 patients enroled from 1125 families, the most frequently observed phenotype was non-syndromic retinitis pigmentosa (40.8%). A genetically confirmed diagnosis was achieved in 72.3% of families. Consanguinity was observed in one-fifth of cases, contributing to a higher frequency of homozygous variants within this cohort. Disease-causing genotypes were distributed across 136 different genes, with ABCA4 (13.0%), EYS (10.0%) and USH2A (6.9%) being the most frequently mutated genes. Overall, these results from a nationwide cohort significantly advance our understanding of the clinical and genetic spectrum of IRDs in Portugal, laying the groundwork for future studies to identify patients eligible for targeted therapies and to describe the natural history of these diseases.

Purpose: Retinitis pigmentosa (RP) comprises a genetically and clinically heterogeneous group of inherited retinal degenerations, where 20–30% of patients exhibit extra-ocular manifestations (syndromic RP). Understanding the genetic profile of RP has important implications for disease prognosis and genetic counseling. This study aimed to characterize the genetic profile of syndromic RP in Portugal. Methods: Multicenter, retrospective cohort study. Six Portuguese healthcare providers identified patients with a clinical diagnosis of syndromic RP and available genetic testing results. All patients had been previously subjected to a detailed ophthalmologic examination and clinically oriented genetic testing. Genetic variants were classified according to the American College of Medical Genetics and Genomics; only likely pathogenic or pathogenic variants were considered relevant for disease etiology. Results: One hundred and twenty-two patients (53.3% males) from 100 families were included. Usher syndrome was the most frequent diagnosis (62.0%), followed by Bardet-Biedl (19.0%) and Senior-Løken syndromes (7.0%). Deleterious variants were identified in 86/100 families for a diagnostic yield of 86.0% (87.1% for Usher and 94.7% for Bardet-Biedl). A total of 81 genetic variants were identified in 25 different genes, 22 of which are novel. USH2A and MYO7A were responsible for most type II and type I Usher syndrome cases, respectively. BBS1 variants were the cause of Bardet-Biedl syndrome in 52.6% of families. Best-corrected visual acuity (BCVA) records were available at baseline and last visit for 99 patients (198 eyes), with a median follow-up of 62.0 months. The mean BCVA was 56.5 ETDRS letters at baseline (Snellen equivalent ~ 20/80), declining to 44.9 ETDRS letters (Snellen equivalent ~ 20/125) at the last available follow-up (p < 0.001). Conclusion: This is the first multicenter study depicting the genetic profile of syndromic RP in Portugal, thus contributing toward a better understanding of this heterogeneous disease group. Usher and Bardet-Biedl syndromes were found to be the most common types of syndromic RP in this large Portuguese cohort. A high diagnostic yield was obtained, highlighting current genetic testing capabilities in providing a molecular diagnosis to most affected individuals. This has major implications in determining disease-related prognosis and providing targeted genetic counseling for syndromic RP patients in Portugal.