Journal article
Demonstration of the pathogenicity of a common non-exomic mutation in ABCA4 using iPSC-derived retinal organoids and retrospective clinical data
Human molecular genetics, Vol.33(16), pp.1379-1390
08/15/2024
DOI: 10.1093/hmg/ddad176
PMCID: PMC11305681
PMID: 37930186
Abstract
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.
Details
- Title: Subtitle
- Demonstration of the pathogenicity of a common non-exomic mutation in ABCA4 using iPSC-derived retinal organoids and retrospective clinical data
- Creators
- Erin R Burnight - University of IowaBeau J Fenner - University of IowaIan C Han - University of IowaAdam P DeLuca - University of IowaS Scott Whitmore - University of IowaLaura R Bohrer - University of IowaJeaneen L Andorf - University of IowaElliott H Sohn - University of IowaRobert F Mullins - University of IowaBudd A Tucker - University of IowaEdwin M Stone - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.33(16), pp.1379-1390
- DOI
- 10.1093/hmg/ddad176
- PMID
- 37930186
- PMCID
- PMC11305681
- NLM abbreviation
- Hum Mol Genet
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Language
- English
- Electronic publication date
- 10/31/2023
- Date published
- 08/15/2024
- Academic Unit
- The University of Iowa Institute for Vision Research; Iowa Neuroscience Institute; John and Marcia Carver Nonprofit Genetic Testing Laboratory; Fraternal Order of Eagles Diabetes Research Center; Center for Bioinformatics and Computational Biology; Ophthalmology and Visual Sciences
- Record Identifier
- 9984505159702771
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