An Overview of the Genetics of ABCA4 Retinopathies, an Evolving Story

Abstract

Stargardt disease (STGD1) and ABCA4 retinopathies (ABCA4R) are caused by pathogenic variants in the ABCA4 gene inherited in an autosomal recessive manner. The gene encodes an importer flippase protein that prevents the build-up of vitamin A derivatives that are toxic to the RPE. Diagnosing ABCA4R is complex due to its phenotypic variability and the presence of other inherited retinal dystrophy phenocopies. ABCA4 is a large gene, comprising 50 exons; to date >2000 variants have been described. These include missense, nonsense, splicing, structural, and deep intronic variants. Missense variants account for the majority of variants in ABCA4. However, in a significant proportion of patients with an ABCA4R phenotype, a second variant in ABCA4 is not identified. This could be due to the presence of yet unknown variants, or hypomorphic alleles being incorrectly classified as benign, or the possibility that the disease is caused by a variant in another gene. This underlines the importance of accurate genetic testing. The pathogenicity of novel variants can be predicted using in silico programs, but these rely on databases that are not ethnically diverse, thus highlighting the need for studies in differing populations. Functional studies in vitro are useful towards assessing protein function but do not directly measure the flippase activity. Obtaining an accurate molecular diagnosis is becoming increasingly more important as targeted therapeutic options become available; these include pharmacological, gene-based, and cell replacement-based therapies. The aim of this review is to provide an update on the current status of genotyping in ABCA4 and the status of the therapeutic approaches being investigated.

Genetic characteristics of 234 Italian patients with macular and cone/cone-rod dystrophy

“…However, ABCA4 is known to exhibit a great variability of phenotypic expressions, which may also depend on other genetic factors, apart from the degree of pathogenicity of the genetic variants predicted by the in silico software or the type of mutation. Genetic variants can also be distributed differently among countries and different ethnic groups and thus influence the pathological phenotype differently; for example, it has been found to be milder among Africans than among Europeans 41 , 42 . This information is important for patient counselling about prognosis.…”

“…Furthermore, obtaining the genetic definition of a disease is mandatory to enter clinical trials as targeted treatment options will be available to patients in the near future. There are several gene therapy-based treatment options for ABCA4 -distrophies that may become available 41 , 43 , while gene therapies for GUCY2D 44 and RPGR 45 were shown to have greatly promising effects in humans.…”

Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis

“…on RP, which includes a shortlist of frequently mutated genes ( USH2A, RPGR, EYS, RHO , and RP1 ) (Verbakel et al, 2018). The large proportion (approximately 4x higher than expected) of probands solved by variants in ABCA4 is likely explained by the extensive efforts on determining the complex pathogenicity of variants in ABCA4 compared to other genes (Al-Khuzaei et al, 2021; Cornelis et al, 2022; Lee et al, 2022). The underrepresentation of variants detected in genes on the X chromosome might be explained by more extensive targeted testing of X-linked IRD genes such as RPGR (prior to smMIPs sequencing) in probands with X-linked diseases.…”

Stargardt Disease Due to an Intronic Mutation in the ABCA4: A Case Report

“…This, in turn, condenses to phosphatidyl-pyridinium bisretinoid and accumulates in the RPE, forming a major component of lipofuscin, which is toxic to this tissue. 7 …”

“…This, in turn, condenses to phosphatidyl-pyridinium bisretinoid and accumulates in the RPE, forming a major component of lipofuscin, which is toxic to this tissue. 7 STGD1 is inherited in an autosomal recessive manner and is caused by mutations in the ABCA4 gene. [1][2][3][4][5][6][7] Made up of 50 exons, ABCA4 is a highly polymorphic gene.…”