Phenotype-genotype correlations in a pseudodominant Stargardt disease pedigree due to a novel ABCA4 deletion-insertion variant causing a splicing defect.
Mol Genet Genomic Med
; 8(7): e1259, 2020 07.
Article
em En
| MEDLINE
| ID: mdl-32627976
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fenótipo
/
Transportadores de Cassetes de Ligação de ATP
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Mutação INDEL
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Doença de Stargardt
Tipo de estudo:
Prognostic_studies
Limite:
Humans
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Male
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Middle aged
Idioma:
En
Revista:
Mol Genet Genomic Med
Ano de publicação:
2020
Tipo de documento:
Article