Genotype-phenotype severity correlation in a multicentric portuguese cohort of abca4-associated retinopathy

Purpose To investigate genotype-phenotype correlations in ABCA4-associated retinopathy and further validate a recently proposed genotype-phenotype correlation model. Design Multicentric, cross-sectional cohort study. Methods Consecutive patients with genetically confirmed ABCA4-associated retinopathy from three Portuguese centres were included. Patients were categorized into distinct phenotype groups according to the degree of hypoautofluorescence and retinal background appearance in ultra-widefield fundus autofluorescence (UW-FAF) imaging. Genotype classification was performed using two criteria: one according to the presence of the p.Gly1961Glu variant, a hypomorphic variant, at least one moderate variant, or two biallelic severe/PVS1 variants (genotype classification A, which corresponds to the newly described criteria); and another one based on the number of null variants identified (genotype classification B). Associations between clinical data and phenotype and genotype groups were analysed. Results A total of 50 patients were included. Significant correlations between age of onset, best-corrected visual acuity (BCVA), and both phenotype and genotype groups were found, with patients in more severe phenotype and genotype categories exhibiting earlier disease onset and poorer visual function (p<0.001; p<0.001; p<0.001; p<0.001, p<0.001; and p=0.004, respectively). Genotype classification A better predicted phenotype severity on UW-AF imaging, demonstrating milder genotypes in patients with less severe phenotypes and more severe genotypes in those with advanced disease (p<0.001). A genotype-phenotype correlation matrix was constructed based on the classification of the two disease-causing variants and their corresponding phenotypic staging. Conclusion Our findings support the utility of the newly described genotype classification in evaluating ABCA4-associated retinopathy phenotype severity, with possible implications in future understanding of the disease genetics and assessment of individual prognosis for patients.