Phenotype–genotype correlations in a pseudodominant Stargardt disease pedigree due to a novel ABCA4 deletion–insertion variant causing a splicing defect. Issue 7 (23rd April 2020)

• Record Type: Journal Article
• Authors: Huang, Di; Thompson, Jennifer A.; Charng, Jason; Chelva, Enid; McLenachan, Samuel; Chen, Shang‐Chih; Zhang, Dan; McLaren, Terri L.; Lamey, Tina M.; Constable, Ian J.; De Roach, John N.; Aung‐Htut, May Thandar; Adams, Abbie; Fletcher, Sue; Wilton, Steve D.; Chen, Fred K.
• Is Part Of: Molecular genetics & genomic medicine. Volume 8:Issue 7(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-04-23
• Subjects: ATP‐binding cassette subfamily A member 4 (ABCA4) -- genotype‐phenotype correlations -- pseudodominant inheritance -- splicing defect -- variant pathogenicity; Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.1259
• Languages: English
• ISSNs: 2324-9269

Abstract

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. Abstract : This work epitomizes the intrafamilial phenotypic variability in a pseudodominant Stargardt disease pedigree and illustrates the use of patient‐derived fibroblasts to evaluate the effect on splicing of a novel ABCA4 indel variant, and as a method for pathogenicity assessment of other novel ABCA4 variants.