Phenotypic appearances in a large ethnically diverse cohort of 178 patients with ABCA4 retinopathy

Abstract

Purpose : Stargardt disease STGD1/ABCA4 retinopathy (ABCA4R) is the commonest childhood onset inherited retinal dystrophy and can show marked phenotypic heterogeneity and is associated with a number of phenocopies. The characteristic phenotypic features of STGD1 are macular atrophy, flecks, and peripapillary sparing. In this study we aim to describe the broader phenotype in a cohort of 178 patients with ABCA4R to characterise further the spectrum of phenotypic features.

Methods : Patients with variants in ABCA4 were identified from the Oxford Medical Genetics laboratory database. Patients were only included if they had at least one retinal image, a minimum of 2 variants in ABCA4, or 1 variant with a phenotype consistent with an ABCA4R. Phenotyping included: colour fundus imaging (Optos or Topcon), fundus autofluorescence imaging (FAF), and optical coherence tomography (OCT). FAF imaging was primarily used to describe the phenotypic features in this study.

Results : The cohort included 151 patients with at least 2 ABCA4 variants and 27 monoallelic patients with phenotype consistent with ABCA4R. Typical phenotypes associated with ABCA4R were identified in 136 biallelic and 25 monoallelic patients and included: abnormal foveal AF with a ring of raised AF and minimal flecks; flecks but no macular atrophy; macular atrophy surrounded by a well confined ring of flecks; macular atrophy with minimal flecks; mottled macular AF; macular atrophy with flecks within the posterior pole; well defined lesion of macular atrophy surrounded by a heterogenous background AF; patchy areas of macular atrophy with a heterogenous background AF; and widespread chorioretinal atrophy. Atypical phenotypes were identified in 15 biallelic patients and 2 monoallelic patients and included macular atrophy surrounded by a ring of raised AF, heterogenous AF throughout the retina, cone rod dystrophy, retinitis pigmentosa, panretinal atrophy, punctate inner choroidopathy type appearance, and atypical foveal changes.

Conclusions : We present an ethnically diverse British cohort of 178 patients with a diagnosis of an ABCA4R demonstrating the wide spectrum of phenotypic features including atypical cases. Recognition of these different phenotypes in ABCA4R is key in diagnosis, with genetic confirmation, and will be important in selection of patients for inclusion for future therapeutic intervention.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.