Phenotype–genotype correlations in a pseudodominant Stargardt disease pedigree due to a novel ABCA4 deletion–insertion variant causing a splicing defect

Di Huang, Jennifer A. Thompson, Jason Charng, Enid Chelva, Samuel McLenachan, Shang Chih Chen, Dan Zhang, Terri L. McLaren, Tina M. Lamey, Ian J. Constable, John N. De Roach, May Thandar Aung-Htut, Abbie Adams, Sue Fletcher, Steve D. Wilton, Fred K. Chen

Research output: Contribution to journalArticle

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. 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. Results: Affected members carrying the novel c.6031_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. 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.

Original languageEnglish
Article numbere1259
JournalMolecular Genetics and Genomic Medicine
Volume8
Issue number7
DOIs
Publication statusPublished - 1 Jul 2020

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  • Projects

    From discovery to therapy in genetic eye diseases

    Mackey, D., Craig, J., Burdon, K., Jamieson, R., Grigg, J., Chen, F., Otlowski, M., Schofield, D., MacGregor, S. & Hewitt, A.

    National Health & Medical Research Council NHMRC

    1/01/1631/12/20

    Project: Research

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