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

2021; Nature Portfolio; Volume: 11; Issue: 1 Linguagem: Inglês

10.1038/s41598-021-81093-y

2045-2322

Irene Perea‐Romero, Gema Gordo, Ionut-Florin Iancu, Marta Del Pozo‐Valero, Berta Almoguera, Fiona Blanco‐Kelly, Ester Carreño, Belén Jimenez‐Rolando, Rosario López‐Rodríguez, Isabel Lorda‐Sánchez, Inmaculada Martín-Mérida, Lucía Pérez de Ayala, Rosa Riveiro-Álvarez, Elvira Rodríguez‐Pinilla, Saoud Tahsin Swafiri, María José Trujillo-Tiebas, Ana Bustamante‐Aragonés, Rocio Cardero‐Merlo, Ruth Fernández‐Sánchez, J. Gallego‐Merlo, Ines Garcia-Vara, Ascensión Gimenez-Pardo, Laura Horcajada-Burgos, Fernando Infantes‐Barbero, Esther Lantero, Miguel Ángel López-Martínez, Andrea Martínez‐Ramas, Lorena Ondo, Marta Rodríguez de Alba, C. Sánchez-Jimeno, C. Vélez-Monsalve, Cristina Villaverde, Olga Zurita, Domingo Aguilera‐Garcia, Jana Aguirre-Lambán, Ana Arteche‐López, Diego Cantalapiedra, Patrícia José, Liliana Galbis-Martinez, Maria García‐Hoyos, Carlos Lombardia, María Isabel López-Molina, Raquel Pérez-Carro, Luciana Rodrigues Jacy da Silva, Carmen Ramos, Rocío Sánchez-Alcudia, Iker Sánchez‐Navarro, Sorina D. Tatu, Elena Vallespín, Elena Aller, Sara Bernal, Maria J. Gamundi, Gema García‐García, Inmaculada Hernan, Teresa Jaijo, Guillermo Antiñolo, Montserrat Baiget, Miguel Carballo, José M. Millán, Diana Valverde, Rando Allikmets, Sandro Banfi, Frans P.M. Cremers, Rob W.J. Collin, Elfride De Baere, Hákon Hákonarson, Susanne Kohl, Carlo Rivolta, Dror Sharon, María Concepción Alonso‐Cerezo, María Juliana Ballesta‐Martínez, Sergi Beltrán, Carmen Benito López, Jaume Catalá‐Mora, Claudio Catalli, Carmen Cotarelo-Pérez, Miguel Fernández‐Burriel, Ana Fontalba-Romero, Enrique Galán‐Gómez, María García‐Barcina, Loida M. Garcia-Cruz, Blanca Gener, Belén Gil-Fournier, Nancy Govea, Encarna Guillén‐Navarro, I. Hernando Acero, Cristina Irigoyen, Silvia Izquierdo Álvarez, Isabel Llano‐Rivas, Maria A. López-Ariztegui, Vanesa López‐González, Fermina Lopez-Grondona, Loreto Martorell, Pilar Mendez-Perez, María Moreno‐Igoa, Raluca Oancea-Ionescu, Francesc Palau, Guiomar Pérez de Nanclares, Feliciano J. Ramos-Fuentes, Raquel Rodríguez‐López, Montserrat Rodríguez-Pedreira, Lydia Rodriguez-Peña, Berta Rodriguez-Sanchez, Jordi Rosell, Noemí Roselló, Raquel Sáez-Villaverde, Alfredo Santana, Irene Valenzuela, Eva Villota-Deleu, Blanca García‐Sandoval, Pablo Mínguez, Almudena Ávila‐Fernández, Marta Cortón, Carmen Ayuso,

Retinal Diseases and Treatments

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.