Abstract
Purpose :
Conclusive genetic diagnoses in inherited retinal diseases remains a major challenge due to the large number of variants of uncertain significance (VUS) identified in genetic testing. This is especially true in ABCA4-related retinopathies with extensive genetic and clinical heterogeneity. Here, we determined the genotypic and phenotypic spectrum of ABCA4 gene variants in Canadian inherited retinal dystrophy patients.
Methods :
This retrospective study evaluated variants in the ABCA4 gene in 56 patients with an inherited retinal dystrophy diagnosis. With informed consent clinical data were obtained from patient examination (visual acuity, direct and indirect ophthalmoscopy, slit lamp biomicroscopy, fundus photography, optical coherence tomography, electroretinography) and previous medical records and was correlated with genotype. Variants were verified against genetic databases and in silico programs were used to assess their pathogenicity. ABCA4 variants classified as VUS were evaluated using a cryo-electron homology model of ABCA4 to predict the impact on protein function.
Results :
Conclusive disease-causing biallelic ABCA4 variants were detected in 40 patients with either Stargardt disease (34 cases), cone-rod dystrophy (3 cases), macular dystrophy (2 cases) or pattern dystrophy (1 case). In another 5 patients, 1 pathogenic variant was paired with a novel variant classified as pathogenic by in silico analysis (2 nonsense, 1 frameshift, 2 splicing variants). In a further 5 patients, a pathogenic variant paired with a novel VUS (4 missense variants and 1 deletion). Based on the protein modeling, 3 of the missense VUS were reclassified as likely pathogenic as they had an effect on protein structure and were evolutionarily conserved from human to zebrafish. The final 6 patients had only a single ABCA4 variant.
Conclusions :
This study expands the genotypic and phenotypic spectrum of ABCA4 disease-associated variants. In total we identified 9 novel ABCA4 variants that were re-classified by in silico analysis and protein modeling to be likely disease-causing, thus extending the conclusive diagnoses in this cohort of patients to 49 (an increase of 16.5%). Computational analysis provides an important tool to evaluate the impact of VUS in ocular disease.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.