Early Molecular Testing for Presumptive Genetic Eye Diseases

Abstract

Background: Genetic eye diseases (GEDs) comprise a heterogeneous group of hereditary and de novo disorders that involve all ocular structures, including the retina, optic nerve, vitreous, anterior segment, and ocular development. Their marked clinical and genetic heterogeneity frequently delays diagnosis and access to genetic counseling, multidisciplinary management, and emerging gene-based therapies. Although ophthalmic deep phenotyping remains essential, we propose an approach that prioritizes genetic analysis, particularly in under-resourced healthcare settings with limited access to advanced imaging and electrophysiological tests. Methods: We conducted a retrospective observational study of 101 consecutive patients with suspected genetic eye diseases. All were evaluated at a tertiary referral center in northeastern Mexico between January 2020 and August 2023 through comprehensive ophthalmologic examination supplemented by optical coherence tomography, visual-field testing, and fundus photography when clinically indicated. All patients were offered early molecular testing while awaiting future tests, such as electrophysiological testing or further referral visits. Molecular testing consisted of an ophthalmology-focused next-generation sequencing multigene panel. Results: The primary outcome was molecular diagnostic yield. A clinically actionable molecular diagnosis was established in 45 patients, corresponding to an overall molecular diagnostic yield of 44.6%. A total of 165 variants were identified, including 70 pathogenic, 16 likely pathogenic, 43 variants of uncertain significance, and 36 likely benign variants. Usher syndrome was the most frequent molecular diagnosis (10/45, 22.2%), comprising nine patients with USH2A-associated Usher syndrome type 2 and one patient with MYO7A-associated Usher syndrome type 1B, followed by Stickler syndrome (8/45, 17.8%), oculocutaneous albinism (3/45, 6.7%), and Alström syndrome (2/45, 4.4%). Autosomal recessive disorders represented the predominant inheritance pattern (68.9%). Conclusions: Our findings support ophthalmology-focused multigene panels as an effective first-line diagnostic strategy for patients with suspected genetic eye diseases. Early molecular testing may shorten the diagnostic odyssey, optimize resource utilization, facilitate precision diagnosis and genetic counseling, and guide future targeted deep phenotypic evaluation, prognosis, and eligibility for emerging gene-specific therapies.