Open AccessPhenotype–genotype correlations in a pseudodominant Stargardt disease pedigree due to a novel ABCA4 deletion–insertion variant causing a splicing defect
Author(s) -
Huang Di,
Thompson Jennifer A.,
Charng Jason,
Chelva Enid,
McLenachan Samuel,
Chen ShangChih,
Zhang Dan,
McLaren Terri L.,
Lamey Tina M.,
Constable Ian J.,
De Roach John N.,
AungHtut May Thandar,
Adams Abbie,
Fletcher Sue,
Wilton Steve D.,
Chen Fred K.
Publication year - 2020
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.1259
Subject(s) - abca4 , stargardt disease , genetics , biology , rna splicing , exon , sanger sequencing , phenotype , gene , mutation , rna
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.