1. Demonstration of the pathogenicity of a common non-exomic mutation in ABCA4 using iPSC-derived retinal organoids and retrospective clinical data.
- Author
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Burnight ER, Fenner BJ, Han IC, DeLuca AP, Whitmore SS, Bohrer LR, Andorf JL, Sohn EH, Mullins RF, Tucker BA, and Stone EM
- Subjects
- Humans, Male, Female, Adult, Retrospective Studies, Retinal Diseases genetics, Retinal Diseases pathology, Alleles, Middle Aged, Genotype, Phenotype, Heterozygote, Organoids metabolism, Organoids pathology, ATP-Binding Cassette Transporters genetics, Mutation, Induced Pluripotent Stem Cells metabolism, Retina metabolism, Retina pathology
- Abstract
Mutations in ABCA4 are the most common cause of Mendelian retinal disease. Clinical evaluation of this gene is challenging because of its extreme allelic diversity, the large fraction of non-exomic mutations, and the wide range of associated disease. We used patient-derived retinal organoids as well as DNA samples and clinical data from a large cohort of patients with ABCA4-associated retinal disease to investigate the pathogenicity of a variant in ABCA4 (IVS30 + 1321 A>G) that occurs heterozygously in 2% of Europeans. We found that this variant causes mis-splicing of the gene in photoreceptor cells such that the resulting protein contains 36 incorrect amino acids followed by a premature stop. We also investigated the phenotype of 10 patients with compound genotypes that included this mutation. Their median age of first vision loss was 39 years, which is in the mildest quintile of a large cohort of patients with ABCA4 disease. We conclude that the IVS30 + 1321 A>G variant can cause disease when paired with a sufficiently deleterious opposing allele in a sufficiently permissive genetic background., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2024
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