July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
New insights into the phenotypic spectrum of PROM1-associated retinopathy
Author Affiliations & Notes
  • Marta del Pozo Valero
    Department of Genetics, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital (IIS-FJD), Madrid, Spain
  • Inmaculada Martin Merida
    Department of Genetics, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital (IIS-FJD), Madrid, Spain
    Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Spain
  • Belen Jimenez Rolando
    Department of Ophthalmology, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital (IIS-FJD), Spain
  • Ana Arteche
    Department of Genetics, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital (IIS-FJD), Madrid, Spain
  • Almudena Avila Fernandez
    Department of Genetics, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital (IIS-FJD), Madrid, Spain
    Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Spain
  • Fiona Blanco Kelly
    Department of Genetics, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital (IIS-FJD), Madrid, Spain
    Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Spain
  • Rosa Riveiro Alvarez
    Department of Genetics, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital (IIS-FJD), Madrid, Spain
  • Caroline Van Cauwenbergh
    Center for Medical Genetics Ghent, Ghent University and Ghent University Hospital, Belgium
  • Elfride De Baere
    Center for Medical Genetics Ghent, Ghent University and Ghent University Hospital, Belgium
  • Carlo Rivolta
    Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, Switzerland
  • Blanca Garcia Sandoval
    Department of Ophthalmology, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital (IIS-FJD), Spain
  • Marta Corton
    Department of Genetics, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital (IIS-FJD), Madrid, Spain
    Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Spain
  • Carmen Ayuso
    Department of Genetics, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital (IIS-FJD), Madrid, Spain
    Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Spain
  • Footnotes
    Commercial Relationships   Marta del Pozo Valero, None; Inmaculada Martin Merida, None; Belen Jimenez Rolando, None; Ana Arteche, None; Almudena Avila Fernandez, None; Fiona Blanco Kelly, None; Rosa Riveiro Alvarez, None; Caroline Van Cauwenbergh, None; Elfride De Baere, None; Carlo Rivolta, None; Blanca Garcia Sandoval, None; Marta Corton, None; Carmen Ayuso, None
  • Footnotes
    Support  CIBERER Grant (06/07/0036), FIS – FEDER (European Regional Development Fund) Grant (PI16/00425)
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 4926. doi:
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      Marta del Pozo Valero, Inmaculada Martin Merida, Belen Jimenez Rolando, Ana Arteche, Almudena Avila Fernandez, Fiona Blanco Kelly, Rosa Riveiro Alvarez, Caroline Van Cauwenbergh, Elfride De Baere, Carlo Rivolta, Blanca Garcia Sandoval, Marta Corton, Carmen Ayuso; New insights into the phenotypic spectrum of PROM1-associated retinopathy. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4926.

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      © ARVO (1962-2015); The Authors (2016-present)

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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.

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