Genetic Correlates of Phenotypic Variability in c.5882G>A p.(Gly1961Glu)-Associated Stargardt Disease

To quantitatively investigate disease progression and genotype-phenotype correlations in Stargardt disease patients harboring the common ABCA4 variant c.5882G>A p.(Gly1961Glu), aiming to evaluate the contribution of second ABCA4 variants to disease severity.

This multicenter study included 77 Stargardt disease patients uniformly carrying the ABCA4 c.5882G>A p.(Gly1961Glu) variant from Nijmegen, Bonn, and Basel. Ellipsoid zone (EZ) loss was measured using automated segmentation of optical coherence tomography images. Progression was assessed with linear mixed-effects models. Disease severity was quantified by the age-at-criterion EZ loss, defined as the estimated age when EZ atrophy reached 6.25 mm², allowing a comparison of the effects of different second alleles.

A total of 52 patients were included in the study. The median age at first observation was 41 years (interquartile range, 27-52 years). The median age at criterion EZ loss across all patients was 43 years (interquartile range, 31-51 years). Substantial variability in the progression of EZ loss was observed among patients despite the shared c.5882G>A p.(Gly1961Glu) genotype. Differences in specific second ABCA4 variants were strongly associated with variation in disease progression, with some variants linked to markedly earlier progression (e.g., c.1957C>T, -50.7 years) and others associated with delayed progression (e.g., c.1648G>A, +19.8 years).

The ABCA4 c.5882G>A p.(Gly1961Glu) variant is associated with substantial interpatient variability in disease severity, heavily influenced by the nature of the second ABCA4 allele. These findings highlight the importance of precise genotypic characterization in prognostic counseling, clinical trial stratification, and the design of targeted gene therapies.