Expanding the Clinical Spectrum of CRB1-Retinopathies: A Novel Genotype-Phenotype Correlation with Macular Dystrophy...

Biallelic pathogenic variants in the CRB1 gene are associated with severe retinal dystrophies, including early onset severe retinal dystrophy/Leber congenital amaurosis (EOSRD/LCA), retinitis pigmentosa (RP), cone-rod dystrophy (CORD), and macular dystrophy (MD). Despite growing research, scant genotype-phenotype correlations have been established. Here, we present two cases involving individuals that presented with cystoid macular oedema and high intraocular pressure, which were later diagnosed as CRB1-MD, demonstrating a mild and stable phenotype. Two unrelated patients of African heritage were included, a 7-year-old female (case 1) and a 25-year-old female (case 2), both presenting with ocular hypertension and cystoid macular oedema. Case 2 had a history of bilateral plateau iris, treated with laser iridotomy. Baseline visual acuity for case 1 was 0.66 logMAR in the right eye and 0.54 logMAR in the left eye. For case 2, visual acuity was recorded as 0.30 logMAR in both eyes. Genetic testing confirmed a homozygous c.2506C>A p.(Pro836Thr) variant in the CRB1 gene in both cases. Longitudinal follow-up over seven years revealed stable visual acuity, improvement of cystoid macular oedema, and effective intraocular pressure control with topical ocular hypotensive therapy. This study establishes a novel genotype-phenotype correlation between the c.2506C>A p.(Pro836Thr) variant and MD, suggesting a mild, stable disease course in homozygous cases. The findings also highlight a potential association of this variant with elevated IOP, expanding the clinical spectrum of CRB1-related ocular conditions. Early genetic diagnosis and regular ophthalmic monitoring are essential to optimise management and identify therapeutic opportunities in patients with mild CRB1-related phenotypes.