Genotype-phenotype severity correlation in a multicentric portuguese cohort of ABCA4-associated retinopathy

Abstract

PurposeTo investigate genotype-phenotype correlations in ABCA4-associated retinopathy and further validate a recently proposed genotype-phenotype correlation model. DesignMulticentric, cross-sectional cohort study. MethodsConsecutive 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. ResultsA 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. ConclusionOur 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.