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      Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications

      research-article
      1 , 2 , 1 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 3 , 3 , 1 , 1 , 2 , 1 , 2 , 1 , 1 , 2 , 1 , 1 , 2 , 1 , 2 , The ESRETNET Study Group, The ERDC Study Group, The Associated Clinical Study Group, 2 , 3 , 1 , 2 , 1 , 2 , 1 , 2 , , 1 , 2 ,
      Scientific Reports
      Nature Publishing Group UK
      Molecular medicine, Genetics research, Clinical genetics, Hereditary eye disease

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Inherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our main goal was to address the genetic landscape of IRD in the largest cohort of Spanish patients reported to date. A retrospective hospital-based cross-sectional study was carried out on 6089 IRD affected individuals (from 4403 unrelated families), referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to the 3951 families with available DNA using different molecular techniques. Overall, 53.2% (2100/3951) of the studied families were genetically characterized, and 1549 different likely causative variants in 142 genes were identified. The most common phenotype encountered is retinitis pigmentosa (RP) (55.6% of families, 2447/4403). The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP cases, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and USH2A and MYO7A in syndromic IRD. Pathogenic variants c.3386G > T (p.Arg1129Leu) in ABCA4 and c.2276G > T (p.Cys759Phe) in USH2A were the most frequent variants identified. Our study provides the general landscape for IRD in Spain, reporting the largest cohort ever presented. Our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations.

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          Most cited references48

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          Retinitis pigmentosa.

          Hereditary degenerations of the human retina are genetically heterogeneous, with well over 100 genes implicated so far. This Seminar focuses on the subset of diseases called retinitis pigmentosa, in which patients typically lose night vision in adolescence, side vision in young adulthood, and central vision in later life because of progressive loss of rod and cone photoreceptor cells. Measures of retinal function, such as the electroretinogram, show that photoreceptor function is diminished generally many years before symptomic night blindness, visual-field scotomas, or decreased visual acuity arise. More than 45 genes for retinitis pigmentosa have been identified. These genes account for only about 60% of all patients; the remainder have defects in as yet unidentified genes. Findings of controlled trials indicate that nutritional interventions, including vitamin A palmitate and omega-3-rich fish, slow progression of disease in many patients. Imminent treatments for retinitis pigmentosa are greatly anticipated, especially for genetically defined subsets of patients, because of newly identified genes, growing knowledge of affected biochemical pathways, and development of animal models.
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            Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases

            One of the major questions in human genetics is what percentage of individuals in the general population carry a disease-causing mutation. Based on publicly available information on genotypes from six main world populations, we created a database including data on 276,921 sequence variants, present within 187 genes associated with autosomal recessive (AR) inherited retinal diseases (IRDs). Assessment of these variants revealed that 10,044 were categorized as disease-causing mutations. We developed an algorithm to compute the gene-specific prevalence of disease, as well as the mutational burden in healthy subjects. We found that the genetic prevalence of AR-IRDs corresponds approximately to 1 case in 1,380 individuals, with 5.5 million people expected to be affected worldwide. In addition, we calculated that unaffected carriers of mutations are numerous, ranging from 1 in 2.26 individuals in Europeans to 1 in 3.50 individuals in the Finnish population. Our analysis indicates that about 2.7 billion people worldwide (36% of the population) are healthy carriers of at least one mutation that can cause AR-IRD, a value that is probably the highest across any group of Mendelian conditions in humans.
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              Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa.

              Night blindness is an early symptom of retinitis pigmentosa. The rod photoreceptors are responsible for night vision and use rhodopsin as the photosensitive pigment. We found three mutations in the human rhodopsin gene; each occurred exclusively in the affected members of some families with autosomal dominant retinitis pigmentosa. Two mutations were C-to-T transitions involving separate nucleotides of codon 347; the third was a C-to-G transversion in codon 58. Each mutation corresponded to a change in one amino acid residue in the rhodopsin molecule. None of these mutations were found in 106 unrelated normal subjects who served as controls. When the incidence of these three mutations was added to that of a previously reported mutation involving codon 23, 27 of 150 unrelated patients with autosomal dominant retinitis pigmentosa (18 percent) were found to carry one of these four defects in the rhodopsin gene. All 27 patients had abnormal rod function on monitoring of their electroretinograms. It appears that patients with the mutation involving codon 23 probably descend from a single ancestor. In some patients with autosomal dominant retinitis pigmentosa, the disease is caused by one of a variety of mutations of the rhodopsin gene.
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                Author and article information

                Contributors
                mcorton@quironsalud.es
                cayuso@fjs.es
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                15 January 2021
                15 January 2021
                2021
                : 11
                : 1526
                Affiliations
                [1 ]GRID grid.419651.e, Department of Genetics, , Instituto de Investigación Sanitaria-Hospital Universitario Fundación Jiménez Díaz, ; Madrid, Spain
                [2 ]GRID grid.413448.e, ISNI 0000 0000 9314 1427, Center for Biomedical Network Research on Rare Diseases (CIBERER), , Instituto de Salud Carlos III, ; Madrid, Spain
                [3 ]GRID grid.419651.e, Department of Ophthalmology, , Instituto de Investigación Sanitaria-Hospital Universitario Fundación Jiménez Díaz, ; Madrid, Spain
                [4 ]GRID grid.84393.35, ISNI 0000 0001 0360 9602, Research Group on Molecular, Cellular and Genomical Medicine, Instituto de Investigación Sanitaria La Fe (IIS La Fe), ; Valencia, Valencian Community Spain
                [5 ]GRID grid.411251.2, ISNI 0000 0004 1767 647X, Clinical Genetics Department, , Instituto de Investigación Sanitaria Hospital Universitario de la Princesa, Madrid, ; Madrid, Spain
                [6 ]GRID grid.411372.2, ISNI 0000 0001 0534 3000, Medical Genetics Unit, Pediatrics Service, , Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, ; Murcia, Murcia Spain
                [7 ]GRID grid.11478.3b, CNAG-CRG, Center for Genomic Regulation, The Barcelona Institute of Science and Technology, ; Barcelona, Catalonia Spain
                [8 ]GRID grid.411457.2, Genetics Section, , Hospital Universitario Carlos Haya, ; Málaga, Andalusia Spain
                [9 ]GRID grid.413396.a, ISNI 0000 0004 1768 8905, Department of Genetics, , Hospital de la Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, ; Barcelona, Catalonia Spain
                [10 ]GRID grid.411160.3, ISNI 0000 0001 0663 8628, Ophthalmology Service, , Hospital Sant Joan de Déu, ; Barcelona, Catalonia Spain
                [11 ]GRID grid.411232.7, ISNI 0000 0004 1767 5135, Department of Medical Genetics, , Hospital Universitario Cruces, ; Bilbao, Basque Country Spain
                [12 ]GRID grid.411068.a, ISNI 0000 0001 0671 5785, Clinical Genetics Unit, , Hospital Universitario Clínico San Carlos, Madrid, ; Madrid, Spain
                [13 ]Genetics Unit, Hospital de Mérida, Mérida, Badajoz, Extremadura Spain
                [14 ]GRID grid.411325.0, ISNI 0000 0001 0627 4262, Genetics Service, , Hospital Universitario Marqués de Valdecilla (HUMV), ; Santander, Cantabria Spain
                [15 ]Clinical Genetics Unit, Pediatrics Service, Hospital Universitario de Badajoz, Badajoz, Extremadura Spain
                [16 ]GRID grid.414584.8, ISNI 0000 0004 1770 3095, Molecular Genetics Unit, , Hospital de Terrassa, Consorci Sanitari de Terrassa, ; Terrassa, Catalonia Spain
                [17 ]Genetics Unit, Hospital Universitario de Basurto, Osakidetza Basque Health Service, Bilbao, Basque Country Spain
                [18 ]Clinical Genetics Unit, Complejo Hospitalario Insular-Materno Infantil, Las Palmas de Gran Canaria, Canary Islands, Spain
                [19 ]GRID grid.411244.6, ISNI 0000 0000 9691 6072, Department of Genetics, , Hospital Universitario de Getafe, ; Madrid, Madrid Spain
                [20 ]GRID grid.411164.7, ISNI 0000 0004 1796 5984, Genetics Unit, Hospital Son Espases, Palma de Mallorca, ; Balearic Islands, Spain
                [21 ]GRID grid.411052.3, ISNI 0000 0001 2176 9028, Genetics Deparment, , Hospital Universitario Central de Asturias, ; Oviedo, Asturias Spain
                [22 ]GRID grid.414651.3, Department of Ophthalmology, , Hospital Universitario de Donostia, ; San Sebastián, Basque Country Spain
                [23 ]GRID grid.432380.e, Division of Neurosciences, , Biodonostia Health Research Institute, ; San Sebastián, Basque Country Spain
                [24 ]GRID grid.11480.3c, ISNI 0000000121671098, Department of Ophthalmology, , University of the Basque Country-UPV/EHU, ; Vizcaya, Basque Country Spain
                [25 ]GRID grid.411106.3, ISNI 0000 0000 9854 2756, Clinical Genetics Department, , Hospital Universitario Miguel Servet (HUMS), ; Zaragoza, Aragon Spain
                [26 ]GRID grid.438280.5, Cellular Therapy Service, Blood and Tissue Bank, ; Building Dr. Frederic Duran I Jordà, Barcelona, Catalonia Spain
                [27 ]GRID grid.430994.3, ISNI 0000 0004 1763 0287, Musculoskeletal Tissue Engineering Group, , Vall D’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, ; Barcelona, Catalonia Spain
                [28 ]GRID grid.497559.3, Department of Medical Genetics, , Complejo Hospitalario de Navarra (CHN), ; Pamplona, Navarre Spain
                [29 ]Navarra Institute for Health Research (IdiSNA), Pamplona, Navarre Spain
                [30 ]GRID grid.411160.3, ISNI 0000 0001 0663 8628, Molecular Genetics Unit, , Hospital Sant Joan de Deu, ; Barcelona, Catalonia Spain
                [31 ]Molecular (Epi)Genetic Lab, Bioaraba Health Research Institute, Araba University Hospital, Vitoria-Gasteiz, Alava, Basque Country Spain
                [32 ]GRID grid.11205.37, ISNI 0000 0001 2152 8769, Clinical Genetics and Functional Genomics Unit, Pediatrics Service, Hospital Clinico Universitario “Lozano Blesa”, Facultad de Medicina, , Universidad de Zaragoza, ; Zaragoza, Aragon Spain
                [33 ]GRID grid.106023.6, ISNI 0000 0004 1770 977X, Department of Clinical Analysis, , Hospital Universitario General de Valencia, ; Valencia, Valencian Community Spain
                [34 ]GRID grid.411066.4, ISNI 0000 0004 1771 0279, Genetics Unit, , Hospital Materno Infantil Teresa Herrera, Hospital Universitario de A Coruña, A Coruña, ; Galicia, Spain
                [35 ]Instituto Investigación Illes Balears (IDISBA), Palma de Mallorca, Balearic Islands Spain
                [36 ]GRID grid.413396.a, ISNI 0000 0004 1768 8905, Department of Ophthalmology, , Hospital de la Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, ; Barcelona, Catalonia Spain
                [37 ]GRID grid.414651.3, Department of Genetics, , Hospital Universitario Donostia, ; San Sebastian, Basque Country Spain
                [38 ]GRID grid.411083.f, ISNI 0000 0001 0675 8654, Genetics Unit, , Hospital Universitari Vall D’Hebron, ; Barcelona, Catalonia Spain
                [39 ]Instituto Oftalmológico Fernández-Vega, Oviedo, Asturias Spain
                [40 ]GRID grid.21729.3f, ISNI 0000000419368729, Department of Ophthalmology, , Columbia University, ; New York, NY USA
                [41 ]GRID grid.21729.3f, ISNI 0000000419368729, Department of Pathology and Cell Biology, , Columbia University, ; New York, NY USA
                [42 ]GRID grid.9841.4, ISNI 0000 0001 2200 8888, Medical Genetics, Department of Precision Medicine, , Università degli Studi della Campania ‘Luigi Vanvitelli’, ; Naples, Italy
                [43 ]GRID grid.410439.b, ISNI 0000 0004 1758 1171, Telethon Institute of Genetics and Medicine, ; Pozzuoli, Italy
                [44 ]GRID grid.10417.33, ISNI 0000 0004 0444 9382, Department of Human Genetics, , Radboud University Medical Center, ; Nijmegen, The Netherlands
                [45 ]GRID grid.10417.33, ISNI 0000 0004 0444 9382, Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, , Radboud University Medical Center, ; Nijmegen, The Netherlands
                [46 ]GRID grid.5342.0, ISNI 0000 0001 2069 7798, Center for Medical Genetics Ghent (CMGG), , Ghent University and Ghent University Hospital, ; Ghent, Belgium
                [47 ]GRID grid.239552.a, ISNI 0000 0001 0680 8770, Center for Applied Genomics, , Children’s Hospital of Philadelphia, ; Philadelphia, PA USA
                [48 ]GRID grid.239552.a, ISNI 0000 0001 0680 8770, Division of Human Genetics, , Children’s Hospital of Philadelphia, ; Philadelphia, PA USA
                [49 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Department of Pediatrics, Perelman School of Medicine, , University of Pennsylvania, ; Philadelphia, PA USA
                [50 ]GRID grid.10392.39, ISNI 0000 0001 2190 1447, Institute for Ophthalmic Research, Center for Ophthalmology, , University of Tübingen, ; Tübingen, Germany
                [51 ]GRID grid.508836.0, Clinical Research Center, Institute of Molecular and Clinical Ophthalmology Basel (IOB), ; Basel, Switzerland
                [52 ]GRID grid.410567.1, Department of Ophthalmology, , University Hospital Basel, ; Basel, Switzerland
                [53 ]GRID grid.9918.9, ISNI 0000 0004 1936 8411, Department of Genetics and Genome Biology, , University of Leicester, ; Leicester, UK
                [54 ]GRID grid.9619.7, ISNI 0000 0004 1937 0538, Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, , The Hebrew University of Jerusalem, ; Jerusalem, Israel
                [55 ]GRID grid.9224.d, ISNI 0000 0001 2168 1229, Department of Maternofoetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS), , University Hospital Virgen del Rocío-CSIC-University of Seville, ; Seville, Spain
                [56 ]GRID grid.6312.6, ISNI 0000 0001 2097 6738, Department of Biochemistry, Genetics and Immunology, Facultad de Biología, , Universidad de Vigo, ; Pontevedra, Galicia Spain
                [57 ]Research Group on Rare Diseases and Pediatric Medicine, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Vigo, Galicia Spain
                [58 ]GRID grid.6312.6, ISNI 0000 0001 2097 6738, Centro de Investigaciones Biomédicas (CINBIO), , Universidad de Vigo, ; Vigo, Galicia Spain
                Article
                81093
                10.1038/s41598-021-81093-y
                7810997
                33452396
                007c843d-7da6-44e1-bcaa-5614ad23b533
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 28 October 2020
                : 31 December 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004587, Instituto de Salud Carlos III;
                Award ID: FI17/00192
                Award ID: JR17/00020
                Award ID: CP16/00116
                Award ID: CPII17/00006
                Award ID: PI16/00425
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100012818, Comunidad de Madrid;
                Award ID: PEJ-2017-AI/BMD7256
                Award ID: B2017/BMD-3721
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100012006, Fundación Conchita Rábago;
                Funded by: Centro de Investigación Biomédica en Red Enfermedades Raras
                Award ID: 06/07/0036
                Award Recipient :
                Funded by: IIS-FJD Biobank
                Award ID: PT13/0010/0012
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100008530, European Regional Development Fund;
                Funded by: Organización de Ciegos Españoles
                Funded by: FundRef http://dx.doi.org/10.13039/100008054, Fundación Ramón Areces;
                Funded by: University Chair UAM-IIS-FJD of Genomic Medicine
                Categories
                Article
                Custom metadata
                © The Author(s) 2021

                Uncategorized
                molecular medicine,genetics research,clinical genetics,hereditary eye disease
                Uncategorized
                molecular medicine, genetics research, clinical genetics, hereditary eye disease

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