June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
A large-scale genetic analysis of inherited retinal diseases in the Portuguese population identifies a unique pattern of mutations
Author Affiliations & Notes
  • Karolina Kaminska
    Institute of Molecular and Clinical Ophthalmology Basel, Basel, Basel-Stadt, Switzerland
    Department of Ophthalmology, Universitat Basel, Basel, Basel-Stadt, Switzerland
  • Virginie Gisele Peter
    Institute of Molecular and Clinical Ophthalmology Basel, Basel, Basel-Stadt, Switzerland
    Department of Ophthalmology, Universitat Basel, Basel, Basel-Stadt, Switzerland
  • Cristina Santos
    Department of Ophthalmology, Instituto de Oftalmologia Doutor Gama Pinto, Lisboa, Lisboa, Portugal
  • Mathieu Quinodoz
    Institute of Molecular and Clinical Ophthalmology Basel, Basel, Basel-Stadt, Switzerland
    Department of Ophthalmology, Universitat Basel, Basel, Basel-Stadt, Switzerland
  • Francesca Cancellieri
    Institute of Molecular and Clinical Ophthalmology Basel, Basel, Basel-Stadt, Switzerland
    Department of Ophthalmology, Universitat Basel, Basel, Basel-Stadt, Switzerland
  • Katarina Cisarova
    Department of Computational Biology, Universite de Lausanne, Lausanne, Vaud, Switzerland
  • Rosanna Pescini Gobert
    Department of Computational Biology, Universite de Lausanne, Lausanne, Vaud, Switzerland
  • Raquel Rodriguez
    Department of Medical Genetics, Centro Hospitalar Universitario Lisboa Norte EPE, Lisboa, Lisboa, Portugal
  • Sónia Custódio
    Department of Medical Genetics, Centro Hospitalar Universitario Lisboa Norte EPE, Lisboa, Lisboa, Portugal
  • Liliana P Paris
    Department of Ophthalmology, Instituto de Oftalmologia Doutor Gama Pinto, Lisboa, Lisboa, Portugal
  • Ana Berta Sousa
    Department of Medical Genetics, Centro Hospitalar Universitario Lisboa Norte EPE, Lisboa, Lisboa, Portugal
    Laboratory of Basic Immunology, Universidade de Lisboa Faculdade de Medicina, Lisboa, Lisboa, Portugal
  • Luisa Coutinho Santos
    Department of Ophthalmology, Instituto de Oftalmologia Doutor Gama Pinto, Lisboa, Lisboa, Portugal
  • Carlo Rivolta
    Institute of Molecular and Clinical Ophthalmology Basel, Basel, Basel-Stadt, Switzerland
    Department of Ophthalmology, Universitat Basel, Basel, Basel-Stadt, Switzerland
  • Footnotes
    Commercial Relationships   Karolina Kaminska None; Virginie Peter None; Cristina Santos None; Mathieu Quinodoz None; Francesca Cancellieri None; Katarina Cisarova None; Rosanna Gobert None; Raquel Rodriguez None; Sónia Custódio None; Liliana Paris None; Ana Berta Sousa None; Luisa Santos None; Carlo Rivolta None
  • Footnotes
    Support  SNSF Grants 176097 and 204285; Jürg Tschopp MD–PhD Scholarship
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 2792. doi:
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    • Get Citation

      Karolina Kaminska, Virginie Gisele Peter, Cristina Santos, Mathieu Quinodoz, Francesca Cancellieri, Katarina Cisarova, Rosanna Pescini Gobert, Raquel Rodriguez, Sónia Custódio, Liliana P Paris, Ana Berta Sousa, Luisa Coutinho Santos, Carlo Rivolta; A large-scale genetic analysis of inherited retinal diseases in the Portuguese population identifies a unique pattern of mutations. Invest. Ophthalmol. Vis. Sci. 2023;64(8):2792.

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

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Abstract

Purpose : Inherited retinal diseases (IRDs) are rare conditions that can be caused by mutations in more than 250 distinct genes. Such mutations, as well as their patterns of inheritance, are often population-specific. The purpose of this study is to determine the molecular genetic landscape of IRDs in the Portuguese, the only population in Western Europe for which no large-scale analysis of this kind has ever been performed.

Methods : All patients underwent a thorough ophthalmological evaluation. DNA was obtained from peripheral blood or saliva samples and analyzed by genome-wide screens, including but not limited to whole-exome (WES) and whole-genome (WGS) sequencing.

Results : We examined 293 patients from 247 families from Portugal, ascertained at the Ophthalmic Institute Dr. Gama Pinto in Lisbon over 6 years, and identified more than 170 unique mutations (37 previously unreported) in 58 distinct genes. Overall, we detected a very particular distribution of genotypes, different from those described for other populations. The most mutated gene, ABCA4, carried 25 distinct pathogenic variants in 25 individuals, in homozygosis or in various assortments of compound heterozygosity. However, the second most frequent disease gene, EYS, had mainly recurring mutations, and in particular the same genomic deletion was present in as many as 9 different families. Indeed, recurrent variants were also identified in the next most frequently mutated genes: USH2A, RPGR, RHO, PROM1, RDH12, CERKL, RPE65, and RAB28. Intriguingly, almost half of all our index patients carried pathogenic changes in homozygosis, suggesting the presence of multiple founder events. Many had also a slightly elevated degree of overall genomic homozygosity, despite the Portuguese population being genetically heterogeneous and clearly exogamic.

Conclusions : We describe the first clinical and genetic landscape of IRDs in Portugal, uncovering a very particular assortment of mutations, for which recurrent variants and an elevated level of homozygosity are detected in patients within the context of a genetically heterogeneous population. These results contribute to a better understanding of the molecular causes of IRDs globally, but also serve as a basis for future diagnosis and gene-based therapy trials for patients from this region of Europe.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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