ArticleInvestigative ophthalmology & visual science2022
ABCA4 c.859-25A>G, a Frequent Palestinian Founder Mutation Affecting the Intron 7 Branchpoint, Is Associated With Early-Onset Stargardt Disease.
Article in Investigative ophthalmology & visual science, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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5 citing papers in PubMed, 6 citations in OpenAlex.
- First Exonic Cryptic Branchpoint Variant in an Inherited Retinal Degeneration Detected in an IrishGenes · 2026Article
- Personalised genomic strategies improve diagnostic yield in inherited retinal dystrophies: a stepwise, patient-centred approach.Eye (London, England) · 2025Article
- New genetic diagnoses for inherited retinal dystrophies by integrating splicing tools into NGS pipelines.NPJ genomic medicine · 2025Article
- Targeted sequencing and in vitro splice assays shed light on ABCA4-associated retinopathies missing heritability.HGG advances · 2023Article
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17 authors at 9 institutions in 5 countries.
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Abstract
Purpose: The effect of noncoding variants is often unknown in the absence of functional assays. Here, we characterized an ABCA4 intron 7 variant, c.859-25A>G, identified in Palestinian probands with Stargardt disease (STGD) or cone-rod dystrophy (CRD). We investigated the effect of this variant on the ABCA4 mRNA and retinal phenotype, and its prevalence in Palestine. Methods: The ABCA4 gene was sequenced completely or partially in 1998 cases with STGD or CRD. The effect of c.859-25A>G on splicing was investigated in silico using SpliceAI and in vitro using splice assays. Homozygosity mapping was performed for 16 affected individuals homozygous for c.859-25A>G. The clinical phenotype was assessed using functional and structural analyses including visual acuity, full-field electroretinography, and multimodal imaging. Results: The smMIPs-based ABCA4 sequencing revealed c.859-25A>G in 10 Palestinian probands from Hebron and Jerusalem. SpliceAI predicted a significant effect of this putative branchpoint-inactivating variant on the nearby intron 7 splice acceptor site. Splice assays revealed exon 8 skipping and two partial inclusions of intron 7, each having a deleterious effect. Additional genotyping revealed another 46 affected homozygous or compound heterozygous individuals carrying variant c.859-25A>G. Homozygotes shared a genomic segment of 59.6 to 87.9 kb and showed severe retinal defects on ophthalmoscopic evaluation. Conclusions: The ABCA4 variant c.859-25A>G disrupts a predicted branchpoint, resulting in protein truncation because of different splice defects, and is associated with early-onset STGD1 when present in homozygosity. This variant was found in 25/525 Palestinian inherited retinal dystrophy probands, representing one of the most frequent inherited retinal disease-causing variants in West-Bank Palestine.
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