Inherited Retinal Diseases: Natural History and Genotype-Phenotype Correlations

Inherited Retinal Diseases: Natural History and Genotype-Phenotype Correlations, Monocentric Retrospective Observational Study

Inherited Retinal Diseases (IRDs) are a heterogeneous group of genetically based degenerative retinal disorders, representing a major cause of visual impairment and blindness in working-age adults. Despite the approval of the first gene therapy for RPE65-related IRD (voretigene neparvovec) in 2017, most IRDs remain untreatable, though many gene therapies are in development. Effective trial design and therapy development require a deep understanding of disease natural history and genotype-phenotype correlations. Over 270 IRD-associated genes are known (e.g., ABCA4, USH2A, RPGR, PRPH2, BEST1), each linked to distinct phenotypes and clinical progression. This retrospective study analyzes clinical, functional, and imaging data (Optical Coherence Tomography, Fundus Autofluorescence, Microperimetry) from a large, genetically characterized IRD cohort at the IRCCS Ospedale San Raffaele up to December 31, 2025. The aims are to describe natural history, define genotype-phenotype relationships, and identify structural and functional outcome measures useful for future clinical trial endpoints, supporting personalized prognosis and trial design.

Inclusion Criteria:

1. Participant completed at least one ophthalmological and retinal imaging examination at our center.
2. Clinically diagnosed with IRD, as per familiy history, clinical signs or symptoms, retinal imaging findings.
3. Definitive genetic diagnosis of IRD with adequate molecular test

Exclusion Criteria:

1. Affected by other retinal or optic nerve conditions potentially affecting analyses (diabetic retinopathy, glaucoma).
2. History of retinotoxic medications (i.e., hydroxychloroquine, pentosan polysulfate sodium, tamoxifen, ritonavir, didanosine, MEK inhibitors) intake.
3. Unclear genetic diagnosis.
4. Incomplete or inadequate ophthalmological and imaging tests.