IMPG2-related maculopathy

Abstract

Purpose : Mono-allelic IMPG2 variants may be associated with vitelliform macular lesions whereas bi-allelic variants result in retinitis pigmentosa (RP) with early-onset macular atrophy. Here, the phenotype, variability and penetrance of IMPG2-related maculopathy is investigated.

Methods : This cross-sectional study included a comprehensive ophthalmic examination with multimodal retinal imaging, genetic testing, and molecular modeling.

Results : Twenty-four individuals with a mono-allelic IMPG2 variant were included, 4 of whom were relatives of patients with IMPG2-associated RP. In 17 individuals, a distinct maculopathy was present and included foveal elevation with or without subretinal vitelliform material or focal atrophy of the retinal pigment epithelium. Best corrected visual acuity (BCVA) was ≥ 20/50 in the better eye (n=15) and 5 patients were asymptomatic. Longitudinal observation (n=8, up to 19 years) demonstrated stable maculopathy (n=3), partial/complete resorption (n=4) or increase (n=1) of the subretinal material, with overall stable vision (n=6). The remaining 7 individuals (BCVA ≥ 20/25) showed no manifest maculopathy and were identified through segregation analysis. All 7 were asymptomatic, with minimal foveal changes observed on optical coherence tomography in 3 cases. Sixteen different variants were detected, 9 of them truncating. Molecular modeling of five missense variants, c.727G>C, c.1124C>A, c.2816T>A, c.3047T>C and c.3193G>A supported the hypothesis that these have a loss-of-function effect.

Conclusions : Mono-allelic IMPG2 variants may result in haplo-insufficiency manifesting as a maculopathy with variable penetrance and expressivity. Family members of patients with IMPG2-related RP may present with vitelliform lesions. The maculopathy often remains limited to the fovea and is usually not associated with severe visual impairment.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.