Comprehensive analysis of the ABCA4 gene: characterization of new pathogenic variants

Comprehensive analysis of the ABCA4 gene

A great number of patients affected by retinal dystrophies with macular involvement, such as Stargardt's disease, have mutations in ABCA4, a complex and large gene. The aim of this research is to study this gene to improve the diagnosis and treatment of these pathologies.

Research team

Principal: Dr Esther Pomares

Co-researchers: Dr Arnau Navinés (Department of Genetics), and Dr Anniken Burés, Dr Borja Corcóstegui and Dr Rafael Navarro (Department of Retina and Vitreous)


Private donations through the crowdfunding Investigating a Gene (


IMO Foundation's own funds


November 2016 - present

Project description

The vast majority of patients with Stargardt's disease, as well as half of the recessive cases of cone-rod dystrophy, have mutations in the ABCA4 gene. In addition, this gene is also associated with a considerable number of cases of bull’s eye maculopathy and a small number of families with Retinitis Pigmentosa. All this places ABCA4 as a gene with outstanding casuistry in the group of Retinal Dystrophies (RD), and it is for this reason that efforts are being made to design effective therapies on it.

Most of these treatments depend on the type of mutation and the effect it produces, so the study and prior knowledge of the variants associated with these RDs is an essential requirement when developing the most appropriate therapies in each case.

The research and identification of variants in the ABCA4 gene is particularly complex, due to its large size (50 exons or DNA coding regions) and its high allelic heterogeneity (more than 1200 mutations described to date). In addition, it may present pathogenic variants in intronic or regulatory regions,in other words, non-coding regions. In fact, it is estimated that between 15-20% of patients are carriers of at least one mutation in these regions, which cannot be analyzed in conventional genetic studies due to their high complexity.

In a first phase of this project, the research group of the IMO Foundation's molecular biology laboratory carried out a study based on the complete analysis of the 50 exons of the ABCA4 gene in 65 patients. In 23% of the cases only one pathogenic allele could be identified, and for this reason, in a second phase of the project, the study of these non-coding regions was proposed, with the aim of identifying new variants and completing the genetic diagnosis of those patients with a single mutation in ABCA4. To do this, a strategy of analysis of the complete gene was designed, which has allowed to identify new variants in deep intronic regions, in some of the cases.

For this reason, in a second phase of the project, the study of these non-coding regions was proposed, with the aim of identifying new variants and completing the genetic diagnosis of those patients with a single mutation in ABCA4. To this end, a strategy was designed to analyze the complete locus of the gene, allowing the identification of new variants in deep intronic regions in some cases.

Current status of the project

June 2022

The Department of Genetics has achieved a high success rate by having found pathogenic variants in the ABCA4 gene from more than 100 families with clinical manifestations associated with retinal macular dystrophies.These families are classified into different pathologies that affect the majority cells of the macula, in the center of the retina: the cones. Thus, in our cohort, we have families that have Stargardt's Disease (STGD), Cone and Rod Dystrophy (CRD) or FundusFlavimaculatus (FF), among others. In total, 163 pathogenic variants have been identified, of which 17 of them have not been previously described in other affected families of Retinal Dystrophies.

In several of these families, in which a genetic cause for the disease had not previously been found, new pathogenic variants have been found in deep intronic regions that could be responsible for retinal dystrophy.

On the other hand, we have continued to study the models of photoreceptors (cones and rods) and pigment epithelium cells obtained from stem cells (iPS cells) of two patients with Stargardt's disease. In addition, also from these stem cells, we have begun to generate 3D models of this pathology; the retinal organoids, which allow a finer and more precise modeling of the cellular processes that are affected in these patients. 

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