The Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multi-centre Study on behalf of the Foveal Development Investigators Group (FDIG)

Abstract

Purpose : Foveal hypoplasia (FH) is characterised by the continuation of inner retinal layers posterior to the foveola. Varying degrees of FH represent different stages of arrested foveal development. The Leicester Grading System for FH divides typical FH into four grades and an additional grade for atypical FH. The grading system has been applied to various disorders including albinism, idiopathic infantile nystagmus (with or without FRMD7 variants), and PAX6, SLC38A8 and AHR variants. The grading system is used as a diagnostic and prognostic tool. To date, it is unclear whether variants of certain genes are associated with worse foveal morphology and prognosis. Thus, we aimed to perform a comparative multi-centre study to characterise the genotypic and phenotypic spectrum of FH in the aforementioned aetiologies.

Methods : Patients with known genetic associations with FH and nystagmus (n=575) were identified from 10 centres from 8 countries (75.6%), as part of FDIG, or extracted from publicly available datasets from previously reported literature (24.4%). Genetic diagnosis was achieved using targeted panel-based sequencing or exome sequencing. Due to the rarity of AHR variants, we only included cases reported in the literature (n=2). Optical coherence tomography of the fovea was obtained in all subjects.

Results : The most common genetic aetiology for typical FH was albinism (66.1%), followed by PAX6 (22.8%) and SLC38A8 variants (7.1%). FRMD7 (3.7%) and AHR variants (0.4%) were rare causes of FH. All grades of FH were seen in albinism and PAX6 variants. All SLC38A8 cases demonstrated grade 3 or 4 FH. In AHR variants, only grade 3 FH has been reported. In cases of FH and FRMD7 variants only grade 1 FH was observed.

Conclusions : We characterised the phenotypic and genotypic spectrum of FH. Our data suggests that arrested retinal development occurs earlier in SLC38A8 and AHR variants and much later in FRMD7 variants. The defined time-period of foveal developmental arrest for albinism and PAX6 variants appears to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and have significant prognostic and diagnostic value.

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