Genotypic and Phenotypic Insights on 11 Novel Variants in the ABCA4 Gene

Objectives: The aim of this study was to report novel ABCA4 variants detected in a cohort of 259 patients with ABCA4 retinopathy with the intention of improving the diagnostic accuracy for ABCA4 retinopathy and expanding its genetic spectrum. Methods: We retrospectively reviewed 259 patients with ABCA4 retinopathy, comprising 190 patients from the Oxford Cohort and 69 patients from other centres with a clinical diagnosis of ABCA4 retinopathy who were referred for genetic testing. Patients with a phenotype consistent with ABCA4 retinopathy who had a novel ABCA4 variant were included. Phenotyping in the Oxford Cohort included clinical evaluation, retinal imaging, and electrodiagnostic testing. Genetic testing was performed using next-generation sequencing (NGS) and Sanger sequencing. In silico analysis was used to investigate the pathogenicity of novel variants. Results: Eleven novel variants were detected in 12/259 patients, with one variant detected in two unrelated patients. These variants included three missense, four truncating, three splice-site variants, and one exon deletion. The variants were distributed across eight exons and three introns of ABCA4. In silico analysis and phenotype correlation supported the potential pathogenicity of the novel variants. Phenotypes ranged from mild isolated flecks with preserved retinal architecture to extensive chorioretinal degeneration. Conclusions: Despite over 2200 ABCA4 variants being reported to date, a further 11 novel ABCA4 variants were identified in 259 patients using NGS panel-based sequencing and MLPA. The variants were located across the whole ABCA4 gene, emphasising the necessity to sequence the whole gene. Our reporting of these variants expands the known genetic spectrum of ABCA4 retinopathy, contributing to accurate diagnosis in this patient group and the identification of suitable patients for recruitment to potential therapeutic interventions.