scholarly journals Extremely hypomorphic and severe deep intronic variants in the ABCA4 locus result in varying Stargardt disease phenotypes

2018 ◽  
Vol 4 (4) ◽  
pp. a002733 ◽  
Author(s):  
Jana Zernant ◽  
Winston Lee ◽  
Takayuki Nagasaki ◽  
Frederick T. Collison ◽  
Gerald A. Fishman ◽  
...  
Keyword(s):  
Stargardt Disease ◽  
Disease Phenotypes ◽  
Intronic Variants

scholarly journals Prevalence of ABCA4 Deep-Intronic Variants and Related Phenotype in An Unsolved “One-Hit” Cohort with Stargardt Disease

2019 ◽  
Vol 20 (20) ◽  
pp. 5053 ◽  
Author(s):  
Nassisi ◽  
Mohand-Saïd ◽  
Andrieu ◽  
Antonio ◽  
Condroyer ◽  
...  
Keyword(s):  
In Silico ◽  
Cohort Analysis ◽  
Pathogenic Variant ◽  
Stargardt Disease ◽  
Phenotypic Analysis ◽  
Variable Effect ◽  
Mild Phenotype ◽  
Related Phenotype ◽  
Novel Variants ◽  
Intronic Variants

We investigated the prevalence of reported deep-intronic variants in a French cohort of 70 patients with Stargardt disease harboring a monoallelic pathogenic variant on the exonic regions of ABCA4. Direct Sanger sequencing of selected intronic regions of ABCA4 was conducted. Complete phenotypic analysis and correlation with the genotype was performed in case a known intronic pathogenic variant was identified. All other variants found on the analyzed sequences were queried for minor allele frequency and possible pathogenicity by in silico predictions. The second mutated allele was found in 14 (20%) subjects. The three known deep-intronic variants found were c.5196+1137G>A in intron 36 (6 subjects), c.4539+2064C>T in intron 30 (4 subjects) and c.4253+43G>A in intron 28 (4 subjects). Even though the phenotype depends on the compound effect of the biallelic variants, a genotype-phenotype correlation suggests that the c.5196+1137G>A was mostly associated with a mild phenotype and the c.4539+2064C>T with a more severe one. A variable effect was instead associated with the variant c.4253+43G>A. In addition, two novel variants, c.768+508A>G and c.859-245_859-243delinsTGA never associated with Stargardt disease before, were identified and a possible splice defect was predicted in silico. Our study calls for a larger cohort analysis including targeted locus sequencing and 3D protein modeling to better understand phenotype-genotype correlations associated with deep-intronic changes and patients’ selection for clinical trials.

Cost‐effective molecular inversion probe‐based ABCA4 sequencing reveals deep‐intronic variants in Stargardt disease

2019 ◽  
Vol 40 (10) ◽  
pp. 1749-1759 ◽  
Author(s):  
Mubeen Khan ◽  
Stéphanie S. Cornelis ◽  
Muhammad Imran Khan ◽  
Duaa Elmelik ◽  
Eline Manders ◽  
...  
Keyword(s):  
Cost Effective ◽  
Stargardt Disease ◽  
Molecular Inversion Probe ◽  
Intronic Variants

scholarly journals Antisense Oligonucleotide-Based Rescue of Aberrant Splicing Defects Caused by 15 Pathogenic Variants in ABCA4

2021 ◽  
Vol 22 (9) ◽  
pp. 4621
Author(s):  
Tomasz Z. Tomkiewicz ◽  
Nuria Suárez-Herrera ◽  
Frans P. M. Cremers ◽  
Rob W. J. Collin ◽  
Alejandro Garanto
Keyword(s):  
Antisense Oligonucleotide ◽  
Mrna Splicing ◽  
Stargardt Disease ◽  
Aberrant Splicing ◽  
Suitable Candidate ◽  
Pathogenic Variants ◽  
Splice System ◽  
Splicing Defects ◽  
Intronic Variants

The discovery of novel intronic variants in the ABCA4 locus has contributed significantly to solving the missing heritability in Stargardt disease (STGD1). The increasing number of variants affecting pre-mRNA splicing makes ABCA4 a suitable candidate for antisense oligonucleotide (AON)-based splicing modulation therapies. In this study, AON-based splicing modulation was assessed for 15 recently described intronic variants (three near-exon and 12 deep-intronic variants). In total, 26 AONs were designed and tested in vitro using a midigene-based splice system. Overall, partial or complete splicing correction was observed for two variants causing exon elongation and all variants causing pseudoexon inclusion. Together, our results confirm the high potential of AONs for the development of future RNA therapies to correct splicing defects causing STGD1.

scholarly journals Resolving the dark matter of ABCA4 for 1,054 Stargardt disease probands through integrated genomics and transcriptomics

2019 ◽  
Author(s):  
Mubeen Khan ◽  
Stéphanie S. Cornelis ◽  
Marta del Pozo-Valero ◽  
Laura Whelan ◽  
Esmee H. Runhart ◽  
...  
Keyword(s):  
Data Storage ◽  
Single Molecule ◽  
Large Scale ◽  
Cost Effective ◽  
Chromosome 1 ◽  
Stargardt Disease ◽  
Model Study ◽  
Integrated Genomics ◽  
Intronic Variants

ABSTRACTMissing heritability in human diseases represents a major challenge. Although whole-genome sequencing enables the analysis of coding and non-coding sequences, substantial costs and data storage requirements hamper its large-scale use to (re)sequence genes in genetically unsolved cases. The ABCA4 gene implicated in Stargardt disease (STGD1) has been studied extensively for 22 years, but thousands of cases remained unsolved. Therefore, single molecule molecular inversion probes were designed that enabled an automated and cost-effective sequence analysis of the complete 128-kb ABCA4 gene. Analysis of 1,054 unsolved STGD and STGD-like probands resulted in bi-allelic variations in 448 probands. Twenty-seven different causal deep-intronic variants were identified in 117 alleles. Based on in vitro splice assays, the 13 novel causal deep-intronic variants were found to result in pseudo-exon (PE) insertions (n=10) or exon elongations (n=3). Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions that were accompanied by flanking exon deletions. Structural variant analysis revealed 11 distinct deletions, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband. Integrated complete gene sequencing combined with transcript analysis, identified pathogenic deep-intronic and structural variants in 26% of bi-allelic cases not solved previously by sequencing of coding regions. This strategy serves as a model study that can be applied to other inherited diseases in which only one or a few genes are involved in the majority of cases.

scholarly journals ATP-binding cassette subfamily A, member 4 intronic variants c.4773+3A>G and c.5461-10T>C cause Stargardt disease due to defective splicing

2018 ◽  
Vol 96 (7) ◽  
pp. 737-743 ◽  
Author(s):  
Frida Jonsson ◽  
Ida Maria Westin ◽  
Lennart Österman ◽  
Ola Sandgren ◽  
Marie Burstedt ◽  
...  
Keyword(s):  
Atp Binding ◽  
Stargardt Disease ◽  
Intronic Variants ◽  
Atp Binding Cassette
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