Longitudinal study of PROM1 IRD variants and review of the literature

Abstract

Purpose : PROM1 inherited retinal disease can result in significant variability in the clinical phenotype. We reviewed longitudinal follow-up in a cohort of patients with autosomal recessive (AR) and autosomal dominant (AD) forms of PROM1-related disease and systematically reviewed the variants in publicly available databases.

Methods : Identification of patients with pathogenic mutations in PROM1 identified through whole exome sequencing (WES). Respective review of patients’ records, multimodal imaging and electrophysiology. Parameters including duration to diagnosis from symptoms, BCVA and refraction. Spectral domain OCT data including ellipsoid zone, central retinal thickness, and development of complete or incomplete outer retinal outer atrophy. Quantification of atrophy with autofluorescence on ultra widefield retinal imaging.

Systematic review of databases to identify PROM1 variants was performed using ClinVar and the Human Gene Mutation Database (HGMD) as well as MEDLINE and PubMed. Pathogenic, likely pathogenic or variants of unknown significance (VUS), in trans with another variant, were included.

Results : 9 patients, 6 patients with bi-allelic PROM1 variants (3 novel) and 3 with a recurrent heterozygous pathogenic variant were identified.

For bi-allelic variants, 4 were compound heterozygous and 2 were homozygous. Duration of follow-up was 12.25 years (SEM 4.83 years). Median age of onset of symptoms was 11.1years (SEM=1.3 years). For patients it took a median of 10.5 years to develop BCVA <1.0 LogMAR (20/200). This corresponded to the development of complete outer retinal atrophy on OCT. Macular hypoautofluorescence increased at a rate of 0.85mm²per year (5.5 years). Electrophysiology demonstrated early cone dysfunction.

For AD varaints the patients developed macula atrophy there was variation in the phenotype.

72 pathogenic and 22 likely pathogenic variants were identified in the databases. Phenotypic information could be identified in 53 variants encompassing the entire IRD spectrum. Cone-rod and rod-cone dystrophy were the most common. Macula dystrophy was most associated with the AD form of PROM1-related disease due to a recurrent missense heterozygous variant whilst the cone-rod dystrophies were more common with the AR form of disease with biallelic frameshift or premature stop codons.

Conclusions : This cohort demonstrates early cone dysfunction and suggests other potential biomarkers in the natural history of PROM1 IRD.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.