Genotype-Phenotype Correlations in ABCA4 -Associated Retinopathy: Insights From a Spanish Cohort of 245 Patients
Year: 2026
Type: article
Study design: Observational Study
Abstract: Purpose: 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. Methods: 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. Results: 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). Conclusions: 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.
DOI: 10.1167/iovs.67.2.19
Authors: Estefania Cobos, Jaume Català-Mora, Cinthia Aguilera, Marc Biarnés, Laura Distefano, María Antolín-Maté, Ricardo P. Casaroli-Marano, Socorro Alforja, Pilar Barberán-Martínez, José M. Millán, Gema García-García, Juan Francisco Santamaría, Delia Yubero, Cristina Irigoyen, Josep Maria Caminal, Lluis Arias, Zelia Corradi, Frans P. M. Cremers, Cristina Sau, Sara Jordan-Cumplido, Anna Esteve-Garcia
Institutions: Bellvitge University Hospital, Institut d'Investigació Biomédica de Bellvitge, Universitat Autònoma de Barcelona, Vall d'Hebron Hospital Universitari, Instituto de Salud Carlos III, Hospital Clínic de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat de Barcelona, Instituto de Investigación Sanitaria La Fe, Hospital Universitari i Politècnic La Fe, Centre for Biomedical Network Research on Rare Diseases, Hospital Sant Joan de Déu Barcelona, Institut de Recerca Sant Joan de Déu, Donostiako Unibertsitate Ospitalea, Radboud University Medical Center
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,850
Awards: CARACTERIZACIÓN GENÉTICA DE LAS HIPOACUSIAS HEREDITARIAS MEDIANTE LA INTEGRACIÓN DE ESTUDIOS GENÓMICOS Y FUNCIONALES, G434337789, Estudio exhaustivo de las distrofias hereditarias de la retina: mejora del diagnóstico molecular, aproximaciones terapéuticas, ensayos clínicos y medida de su impacto en los pacientes., G6550652810, RETVISION: Del diagnóstico genético molecular a las terapias avanzadas para tratar las enfermedades degenerativas de la retina, G7540734645, G8107497153, European Training Network to Diagnose, Understand and Treat Stargardt Disease, a Frequent Inherited Blinding Disorder
OpenAlex ID: W7128038623