Genotypic and phenotypic spectrum of foveal hypoplasia

Abstract

Purpose : Foveal hypoplasia (FH) is characterised by the continuation of inner retinal layers posterior to the foveola. Varying degrees of FH represent the different stages of arrested development of the fovea. 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 mutations), PAX6 mutations, SLC38A8 mutations and AHR mutations. The grading system is used as a diagnostic and prognostic tool.
To date, it is unclear whether mutations of certain genes are associated with worse foveal morphology and prognosis. Thus, we aimed to perform a comparative study to characterise the genotypic and phenotypic spectrum of FH in the aforementioned genetic aetiologies.

Methods : In this multi-centre study, patients with known genetic associations with FH (n=288) were identified from one centre in UK and two centres in South Korea. Genetic diagnosis was achieved using targeted panel-based sequencing or exome sequencing. Due to the rarity of AHR mutations, we only included cases reported in the literature. Optical coherence tomography of the fovea was obtained in all subjects. Grades of FH (Leicester Grading System) were: Grade 1: shallow foveal pit, presence of outer nuclear layer widening, presence of outer segment (OS) lengthening; grade 2: grade 1 but absence of foveal pit, grade 3: grade 2 but absence of OS lengthening; grade 4: grade 3 but absence of ONL widening.

Results : The most common genetic aetiology for typical FH was albinism (74%), followed by PAX6 mutations (15%) and SLC38A8 mutations (9%). AHR and FRMD7 mutations were rare causes of FH. All grades of FH were seen in albinism and PAX6 mutations. In SLC38A8 mutations, we only observe grade 3 (80%) and grade 4 (20%) FH. In AHR mutations only grade 3 FH has been reported. In cases of FH and FRMD7 mutations only grade 1 FH was observed.

Conclusions : Albinism and PAX6 mutations are associated with much wider spectrum of arrested retinal development, however SLC38A8 mutations, AHR mutations and FRMD7 mutations have much narrower spectrum. Our data suggests that arrested retinal development occurs earlier in development in SLC38A8 and AHR mutations and much later in FRMD7 mutations. However, with albinism and PAX6 mutations the defined time period of foveal developmental arrest is more variable.

This is a 2021 ARVO Annual Meeting abstract.