Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications
Authors: Perea-Romero Irene , Gordo Gema , Iancu Ionut F. , Del Pozo-Valero Marta , Almoguera Berta , Blanco-Kelly Fiona , Carreño Ester , Jimenez-Rolando Belen , Lopez-Rodriguez Rosario , Lorda-Sanchez Isabel , Martin-Merida Inmaculada , Pérez de Ayala Lucia , Riveiro-Alvarez Rosa , Rodriguez-Pinilla Elvira , Tahsin-Swafiri Saoud , Trujillo-Tiebas Maria J. ,   The ESRETNET Study Group, Bustamante-Aragones Ana , Cardero-Merlo Rocio , Fernandez-Sanchez Ruth , Gallego-Merlo Jesus , Garcia-Vara Ines , Gimenez-Pardo Ascension , Horcajada-Burgos Laura , Infantes-Barbero Fernando , Lantero Esther , Lopez-Martinez Miguel A. , Martinez-Ramas Andrea , Ondo Lorena , Rodriguez de Alba Marta , Sanchez-Jimeno Carolina , Velez-Monsalve Camilo , Villaverde Cristina , Zurita Olga , Aguilera-Garcia Domingo , Aguirre-Lamban Jana , Arteche Ana , Cantalapiedra Diego , Fernandez-San Jose Patricia , Galbis-Martinez Liliana , Garcia-Hoyos Maria , Lombardia Carlos , Lopez-Molina Maria I. , Perez-Carro Raquel , Da Silva Luciana R. J. , Ramos Carmen , Sanchez-Alcudia Rocio , Sanchez-Navarro Iker , Tatu Sorina D. , Vallespin Elena , Aller Elena , Bernal Sara , Gamundi Maria J. , Garcia-Garcia Gema , Hernan Inmaculada , Jaijo Teresa , Antiñolo Guillermo , Baiget Montserrat , Carballo Miguel , Millan Jose M. , Valverde Diana ,   The ERDC Study Group, Allikmets Rando , Banfi Sandro , Cremers Frans P. M. , Collin Rob W. J. , De Baere Elfride , Hakonarson Hakon , Kohl Susanne , Rivolta Carlo , Sharon Dror ,   The Associated Clinical Study Group, Alonso-Cerezo Maria C. , Ballesta-Martinez Maria J. , Beltran Sergi , Benito Lopez Carmen , Català-Mora Jaume , Catalli Claudio , Cotarelo-Perez Carmen , Fernandez-Burriel Miguel , Fontalba-Romero Ana , Galán-Gómez Enrique , Garcia-Barcina Maria , Garcia-Cruz Loida M. , Gener Blanca , Gil-Fournier Belen , Govea Nancy , Guillen-Navarro Encarna , Hernando Acero Ines , Irigoyen Cristina , Izquierdo-Álvarez Silvia , Llano-Rivas Isabel , López-Ariztegui Maria A. , Lopez-Gonzalez Vanesa , Lopez-Grondona Fermina , Martorell Loreto , Mendez-Perez Pilar , Moreno-Igoa Maria , Oancea-Ionescu Raluca , Palau-Martinez Francesc , Perez de Nanclares Guiomar , Ramos-Fuentes Feliciano J. , Rodriguez-Lopez Raquel , Rodriguez-Pedreira Montserrat , Rodriguez-Peña Lydia , Rodriguez-Sanchez Berta , Rosell Jordi , Rosello Noemi , Saez-Villaverde Raquel , Santana Alfredo , Valenzuela-Palafoll Irene , Villota-Deleu Eva , Garcia-Sandoval Blanca , Minguez Pablo , Avila-Fernandez Almudena , Corton Marta , Ayuso Carmen 
Published: January 2021

AbstractInherited 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.