Expanded phenotypic spectrum of retinopathies associated with autosomal recessive and dominant mutations in PROM1.

PURPOSE: To describe the genetic and phenotypic characteristics of a cohort of patients with PROM1 variants. DESIGN: Case-case study. METHOD: We screened a cohort of 2216 families with inherited retinal dystrophies using classical molecular techniques and next-generation sequencing approaches. The clinical histories of 25 patients were reviewed to determine age of onset of symptoms, and the results of ophthalmoscopy, best corrected visual acuity, full-field electroretinography, and visual field studies. Fundus autofluorescence and spectral-domain optical coherence tomography were further assessed in 7 patients. RESULTS: PROM1 variants were identified in 32 families. Disease-causing variants were found in 18 autosomal recessive and 4 autosomal dominant families. Monoallelic pathogenic variants or variants of unknown significance were identified in the remaining 10 families. Comprehensive phenotyping of 25 patients from 22 families carrying likely disease-causing variants revealed clinical heterogeneity associated with the PROM1 gene. Most of these patients presented cone-rod dystrophy and some exhibited macular dystrophy or retinitis pigmentosa, while all presented macular damage. Phenotypic association of a dominant splicing variant with late-onset mild maculopathy was established. This variant is one of the 3 likely founder variants identified in our Spanish cohort. CONCLUSIONS: We report the largest cohort of patients with PROM1 variants, describing in detail the phenotype in 25 of them. Interestingly, within the variability of phenotypes due to this gene, macular involvement is a common feature in all patients.