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

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.

• Authors: 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
• Journal: Molecular genetics & genomic medicine (Mol Genet Genomic Med) Vol. 8 Issue 7 Pg. e1259 (07 2020) ISSN: 2324-9269 [Electronic] United States
• PMID: 32627976 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.

Chemical References

• ABCA4 protein, human
• ATP-Binding Cassette Transporters

Topics

• ATP-Binding Cassette Transporters (genetics, metabolism)
• Cells, Cultured
• Genes, Dominant
• Humans
• INDEL Mutation
• Male
• Middle Aged
• Pedigree
• Phenotype
• RNA Splicing
• Stargardt Disease (genetics, pathology)