New insights into the phenotypic spectrum of PROM1-associated retinopathy

Abstract

Purpose : Inherited retinal dystrophy (IRD) refers to a group of progressive and degenerative diseases that affect the photoreceptor cells and lead to visual impairment. One of the genes associated with IRD is PROM1. Disease-causing PROM1 variants have been associated with different phenotypes depending on the pattern of inheritance. We provide a detailed analysis of the genetic and phenotypic characteristics of the PROM1-associated retinopathy in a large cohort of patients, aiming to identify genotype–phenotype correlations and to elucidate the real contribution of this gene to IRD

Methods : PROM1 screening was performed using classical molecular techniques and/or targeted Next-Generation-Sequencing in a cohort of 2216 IRD families, mostly of them of Spanish ancestry. Copy number variation analysis was carried out in unsolved monoallelic cases by customized CGH arrays. Detailed ophthalmic evaluation was performed in 25 patients, including fundus autofluorescence imaging and spectral-domain optical coherence tomography in 7 of them

Results : Thirty-two families presented PROM1 variants, including 14 different likely pathogenic PROM1 variants and 5 different variants of unknown significance (VUS), 10 of which are novel. In total, causative variants were identified in 21 families segregating in autosomal recessive (17) or dominant (4) pattern. Three founder effect variants were found in our Spanish cohort. The phenotyping analysis of 25 patients carrying likely disease-causing PROM1 variants revealed clinical heterogeneity regardless of genotype. This way, most of the patients suffered from cone-rod dystrophy and some patients presented with macular dystrophy or retinitis pigmentosa, all presenting macular damage. A new phenotypic association of a founder monoallelic splicing variant with a late-onset mild maculopathy was established

Conclusions : Our study reports the largest and comprehensive description of genetic and clinical findings in PROM1-retinopathy. The prevalence of PROM1 variants that seems to reliably explain the IRD phenotype in our cohort is about 1%, confirming the idea that this gene is a rare cause of IRD. This study also highlights the great heterogeneity of PROM1-associated phenotypes. Regardless of the initial diagnosis of primary cone or rod loss, all patients with PROM1 disease-causing variants developed a common macular involvement, which should be considered a characteristic phenotypic finding of PROM1

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.