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, results already expected taking into account that the second variant could be located in the intronic and regulatory regions of this same gene.

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

January 2021

Currently, we are working on a cohort of more than 90 families with a known genetic cause in the ABCA4 gene, from which we are characterizing new genotype-phenotype correlations for this gene. 

In parallel, together with another IMO Foundation project, two cellular models obtained from skin biopsies of two patients with Stargardt disease carrying mutations in the ABCA4 gene have been generated. These induced pluripotent cell models generated from these two patients have been further differentiated into the two main cell types of the retina, photoreceptors and retinal pigment epithelium (RPE) cells. The study of these two retinal cell models obtained in the laboratory will allow us to determine and characterize in depth the cellular and molecular causes of retinal dystrophies associated with mutations in the ABCA4 gene.

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