Genotype-Phenotype Correlations in ABCA4-Associated Retinopathy: Insights From a Spanish Cohort of 245 Patients

ABCA4-associated retinopathy includes a broad range of inherited retinal dystrophies (IRDs), marked by notable genetic and phenotypic heterogeneity that complicates diagnosis and counseling. This study aims to evaluate genotype-phenotype correlations to improve clinical management and risk stratification.

In this multicenter, retrospective, cross-sectional study, we analyzed 245 patients with biallelic pathogenic ABCA4 variants from 7 Spanish reference centers. Variants were classified by predicted severity, and patients were stratified into five phenotypic categories based on fundus findings. One-way ANOVA and Fisher's exact test were used to assess group differences. Spearman's correlation evaluated genotype-phenotype associations. Ordinal logistic regression, adjusted for age at symptom onset and disease duration, was used to assess the relationship between genotype severity and fundus phenotype.

The mean age of the patients was 43.6 years. Earlier symptom onset and longer disease duration were significantly associated with more severe phenotypic features (P ≤ 0.0008). Genotype severity correlated with phenotype severity (allele 1: P = 0.0036 and allele 2: P = 0.02). Severe variants were linked to more pronounced phenotypes, whereas milder alleles showed weaker associations. The presence of a predicted null (PVS1) variant in allele 1 significantly correlated with more advanced fundus changes (P = 0.0029).

The severity of ABCA4 variants correlate with the extent of retinal phenotype, emphasizing the importance of early molecular diagnosis. These findings support the refinement of variant classification and highlight the need for further studies to better understand the implications for clinical management and potential therapeutic strategies.