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Phenotype-genotype correlations in a pseudodominant Stargardt disease pedigree due to a novel ABCA4 deletion-insertion variant causing a splicing defect.
- Source :
-
Molecular genetics & genomic medicine [Mol Genet Genomic Med] 2020 Jul; Vol. 8 (7), pp. e1259. Date of Electronic Publication: 2020 Apr 23. - Publication Year :
- 2020
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Abstract
- Background: Deletion-insertion (delins) variants in the retina-specific ATP-binding cassette transporter gene, subfamily A, member 4 (ABCA4) accounts for <1% in Stargardt disease. The consequences of these delins variants on splicing cannot be predicted with certainty without supporting in vitro data.<br />Methods: Candidate ABCA4 variants were revealed by genetic and segregation analysis of a family with pseudodominant Stargardt disease using a commercial panel and Sanger sequencing. RNA extracted from patient-derived fibroblasts was analyzed by RT-PCR to evaluate splicing behavior of the ABCA4 variants.<br />Results: Affected members carrying the novel c.6031&#95;6044delinsAGTATTTAACCAATATTT variant in exon 44 presented with contrasting phenotypes; from early-onset cone-rod dystrophy to late-onset macular dystrophy. This variant resulted in a 56-nucleotide deletion in the mutant allele by activation of a cryptic splice acceptor site which disrupts the reading frame and results in a premature termination codon (p.Ile2003LeufsTer41). If translated, the crucial functional domains near the C-terminus would be truncated from the ABCA4 protein.<br />Conclusion: This work demonstrates the intrafamilial phenotypic variability in a pseudodominant Stargardt disease pedigree and the use of patient-derived fibroblasts to evaluate the effect of a novel ABCA4 delins variant on splicing to complement in silico pathogenicity assessment.<br /> (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)
Details
- Language :
- English
- ISSN :
- 2324-9269
- Volume :
- 8
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Molecular genetics & genomic medicine
- Publication Type :
- Academic Journal
- Accession number :
- 32627976
- Full Text :
- https://doi.org/10.1002/mgg3.1259