Marta Del Pozo-Valero1, Inmaculada Martin-Merida2, Belen Jimenez-Rolando3, Ana Arteche1, Almudena Avila-Fernandez2, Fiona Blanco-Kelly2, Rosa Riveiro-Alvarez1, Caroline Van Cauwenbergh4, Elfride De Baere5, Carlo Rivolta6, Blanca Garcia-Sandoval3, Marta Corton2, Carmen Ayuso7. 1. Department of Genetics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid, Madrid, Spain. 2. Department of Genetics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid, Madrid, Spain; Center for Biomedical Network Research on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain. 3. Department of Ophthalmology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid, Madrid, Spain. 4. Center for Medical Genetics Ghent, Ghent University and Ghent University Hospital, Ghent, Belgium; Department of Ophthalmology, Ghent University and Ghent University Hospital, Ghent, Belgium. 5. Center for Medical Genetics Ghent, Ghent University and Ghent University Hospital, Ghent, Belgium. 6. Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Department of Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom. 7. Department of Genetics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid, Madrid, Spain; Center for Biomedical Network Research on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain. Electronic address: cayuso@fjd.es.
Abstract
PURPOSE: To describe the genetic and phenotypic characteristics of a cohort of patients with PROM1 variants. DESIGN: Case-case study. METHODS: 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 with 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 related to this gene, macular involvement is a common feature in all patients.
PURPOSE: To describe the genetic and phenotypic characteristics of a cohort of patients with PROM1 variants. DESIGN: Case-case study. METHODS: 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 with 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 related to this gene, macular involvement is a common feature in all patients.
Authors: Marta Del Pozo-Valero; Rosa Riveiro-Alvarez; Inmaculada Martin-Merida; Fiona Blanco-Kelly; Saoud Swafiri; Isabel Lorda-Sanchez; Maria José Trujillo-Tiebas; Ester Carreño; Belen Jimenez-Rolando; Blanca Garcia-Sandoval; Marta Corton; Almudena Avila-Fernandez; Carmen Ayuso Journal: Invest Ophthalmol Vis Sci Date: 2022-02-01 Impact factor: 4.799