ArticleHuman molecular genetics2021
Cis-acting modifiers in the ABCA4 locus contribute to the penetrance of the major disease-causing variant in Stargardt disease.
Article in Human molecular genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 55 citations in OpenAlex.
- [Stargardt disease (ABCA4-asssociated retinopathy): Overview of clinical aspects, classification and differential diagnoses].Die Ophthalmologie · 2026Review
- A comparative survey of functional evidence use in hearing and vision loss genetics.Communications medicine · 2026Article
- Comprehensive genomic analysis of non-BRCA familial breast cancer in an Arab population.NPJ breast cancer · 2026Article
- More insights from Abca4The Journal of biological chemistry · 2026Article
- Genotype-Phenotype Correlations in ABCA4-Associated Retinopathy: Insights From a Spanish Cohort of 245 Patients.Investigative ophthalmology & visual science · 2026Article
- Genetic Correlates of Phenotypic Variability in c.5882G>A p.(Gly1961Glu)-Associated Stargardt Disease.Investigative ophthalmology & visual science · 2026Article
- De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa.Nature genetics · 2026Article
- Characterization of the Subclinical Perilesional Zone in the Macula of Early-Stage ABCA4 Disease.Translational vision science & technology · 2025Article
- Stargardt's Disease: Molecular Pathogenesis and Current Therapeutic Landscape.International journal of molecular sciences · 2025Review
- Investigation of ABCA4 Missense Variants and Potential Small Molecule Rescue in Retinal Organoids.Investigative ophthalmology & visual science · 2025Article
- Generation of a compound heterozygous ABCA4 rat model with pathological features of STGD1.Human molecular genetics · 2025Article
- Unravelling genotype-phenotype correlations in Stargardt disease using patient-derived retinal organoids.Cell death & disease · 2025Article
- High-efficiency base editing in the retina in primates and human tissues.Nature medicine · 2025Article
- De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa.medRxiv : the preprint server for health sciences · 2025Article
- ABCA4 Deep Intronic Variants Contributed to Nearly Half of Unsolved Stargardt Cases With a Milder Phenotype.Investigative ophthalmology & visual science · 2025Article
- ABCA4 c.5461-6T>C Causes Stargardt Disease Through Exon Skipping.Advances in experimental medicine and biology · 2025Article
- Assessment of ABCA4 Genetic Variants: Current Landscape and Future Prospects.Advances in experimental medicine and biology · 2025Review
- Article
- Functional Characterization of ABCA4 Missense Variants Aids Variant Interpretation and Phenotype Prediction in Patients With ABCA4-Retinal Dystrophies.Investigative ophthalmology & visual science · 2024Article
- Late-Onset Slowly Progressing Cone/Macular Dystrophy in Patients With the Biallelic Hypomorphic Variant p.Arg1933Ter in RP1.Translational vision science & technology · 2024Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
Over 1200 variants in the ABCA4 gene cause a wide variety of retinal disease phenotypes, the best known of which is autosomal recessive Stargardt disease (STGD1). Disease-causing variation encompasses all mutation categories, from large copy number variants to very mild, hypomorphic missense variants. The most prevalent disease-causing ABCA4 variant, present in ~ 20% of cases of European descent, c.5882G > A p.(Gly1961Glu), has been a subject of controversy since its minor allele frequency (MAF) is as high as ~ 0.1 in certain populations, questioning its pathogenicity, especially in homozygous individuals. We sequenced the entire ~140Kb ABCA4 genomic locus in an extensive cohort of 644 bi-allelic, i.e. genetically confirmed, patients with ABCA4 disease and analyzed all variants in 140 compound heterozygous and 10 homozygous cases for the p.(Gly1961Glu) variant. A total of 23 patients in this cohort additionally harbored the deep intronic c.769-784C > T variant on the p.(Gly1961Glu) allele, which appears on a specific haplotype in ~ 15% of p.(Gly1961Glu) alleles. This haplotype was present in 5/7 of homozygous cases, where the p.(Gly1961Glu) was the only known pathogenic variant. Three cases had an exonic variant on the same allele with the p.(Gly1961Glu). Patients with the c.[769-784C > T;5882G > A] complex allele exhibit a more severe clinical phenotype, as seen in compound heterozygotes with some more frequent ABCA4 mutations, e.g. p.(Pro1380Leu). Our findings indicate that the c.769-784C > T variant is major cis-acting modifier of the p.(Gly1961Glu) allele. The absence of such additional allelic variation on most p.(Gly1961Glu) alleles largely explains the observed paucity of affected homozygotes in the population.
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