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

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.

Figure 1

IRD affected cases distribution and estimated prevalence in Spain. (A) Distribution of RP/NON-RP affected cases across Spain. Total cases: 6089 (known Spanish origin: 4668; unknown origin: 1421). Spanish map modified using image editor from https://www.veomapas.com/mapa-mudo-de-las-comunidades-autonomas-de-espana-m103.html. (B) IRD estimated prevalence in Spanish regions. Data was obtained from the number of cases we had in our Hospital Service and the recorded population in the different regions. *Inconclusive data.

Figure 2

“A priori” and final classification of IRD affected cases. (A) “A priori” classification of IRD families with data obtained from the clinical and family history of the patients, before performing molecular tests: NON-RP (I), RP (II), and syndromic IRD (III), and subclassification according to the inheritance type in case of RP and NON-RP, and type of syndrome in case of syndromic IRD. Data obtained with the clinical and familiar history of the patients, before performing molecular tests. AD Autosomal Dominant, AR autosomal recessive, S sporadic, XL X-linked. (B) Proportion of genetically solved NON-RP, RP, syndromic IRD and total IRD. The diagnostic ratio in the different group of NON-RP and RP by the type of “a priori” inheritance and in the different group of syndromic IRD by type of syndrome is indicated. (C) Genetically solved families. Comparison of inheritance classification before (light gray) and after (dark gray) the molecular study was performed.

Figure 3

Classification of mutated genes in the genetically solved NON-RP affected cases. Below each gene is given the percentage that each gene was mutated in the cohort. Total characterized families: AD-NON-RP: 121; AR-NON-RP: 544; XL-NON-RP: 89.

Figure 4

Classification of mutated genes in the genetically solved RP affected cases. Below each gene is given the percentage that each gene was mutated in the cohort. Total characterized families: AD-RP: 207; AR-RP: 666; XL-RP: 165.

Figure 5

Classification of mutated genes in the genetically solved syndromic IRD affected cases. Below each gene is given the percentage that each gene was mutated in the cohort. Total characterized families: Usher I: 56; Usher II: 145; Others (including atypical Usher): 107.