☆ 4.7 Article

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

SCIENTIFIC REPORTS (2021)

Journal

SCIENTIFIC REPORTS

Volume 11, Issue 1, Pages -

Publisher

NATURE PORTFOLIO

DOI: 10.1038/s41598-021-81093-y

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Funding

Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Health (FIS) [PI16/00425, PI19/00321]
Centro de Investigacion Biomedica en Red Enfermedades Raras (CIBERER) [06/07/0036]
IIS-FJD BioBank [PT13/0010/0012]
Comunidad de Madrid (CAM, RAREGenomics Project) [B2017/BMD-3721]
European Regional Development Fund (FEDER)
Organizacion Nacional de Ciegos Espanoles (ONCE)
Fundacion Ramon Areces
Fundacion Conchita Rabago
University Chair UAM-IIS-FJD of Genomic Medicine
ISCIII [FI17/00192, JR17/00020, CP16/00116, CPII17/00006]
Comunidad de Madrid (CAM) [PEJ-2017-AI/BMD7256]

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Abstract

This study investigated the genetic landscape of inherited retinal diseases (IRDs) in Spain, involving 6089 patients from 4403 unrelated families. The most common phenotype identified was retinitis pigmentosa (RP), with several genes such as PRPH2, ABCA4, and RS1 being recurrently mutated across different types of IRD.

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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Updating the Genetic Landscape of Inherited Retinal Dystrophies

Belen Garcia Bohorquez, Elena Aller, Ana Rodriguez Munoz, Teresa Jaijo, Gema Garcia Garcia, Jose M. Millan

Summary: Inherited retinal dystrophies (IRD) are a group of diseases with high genetic and clinical variability, making genetic diagnosis challenging. Next generation sequencing has greatly improved diagnostic accuracy, identifying novel mutations and enabling accurate genetic counseling. The study identified multiple pathogenic variants and highlighted the importance of including deep-intronic regions in gene panel design for effective genetic diagnosis.

FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY (2021)