2014
DOI: 10.1093/hmg/ddu396
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Analysis of the ABCA4 genomic locus in Stargardt disease

Abstract: Autosomal recessive Stargardt disease (STGD1, MIM 248200) is caused by mutations in the ABCA4 gene. Complete sequencing of ABCA4 in STGD patients identifies compound heterozygous or homozygous disease-associated alleles in 65-70% of patients and only one mutation in 15-20% of patients. This study was designed to find the missing disease-causing ABCA4 variation by a combination of next-generation sequencing (NGS), array-Comparative Genome Hybridization (aCGH) screening, familial segregation and in silico analys… Show more

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Cited by 114 publications
(165 citation statements)
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“…WES of patients with 0 ABCA4 mutations has uncovered causal genes in ~70% of cases with ABCA4 -like phenotypes, including known retinal disease genes ( CRB1, CRX , etc)11 13 and new genes ( RAB28, RDH11 ) 10 12. However, despite all these advances, the second causative mutation in most patients with 1 and 0 ABCA4 alleles remains unidentified following complete sequencing 8. This study demonstrates that some known, frequent ABCA4 variants, which have been considered benign due to high minor allele frequency (MAF) in the general population, are in fact hypomorphic alleles, which result in disease expression under certain conditions.…”
Section: Introductionmentioning
confidence: 90%
See 1 more Smart Citation
“…WES of patients with 0 ABCA4 mutations has uncovered causal genes in ~70% of cases with ABCA4 -like phenotypes, including known retinal disease genes ( CRB1, CRX , etc)11 13 and new genes ( RAB28, RDH11 ) 10 12. However, despite all these advances, the second causative mutation in most patients with 1 and 0 ABCA4 alleles remains unidentified following complete sequencing 8. This study demonstrates that some known, frequent ABCA4 variants, which have been considered benign due to high minor allele frequency (MAF) in the general population, are in fact hypomorphic alleles, which result in disease expression under certain conditions.…”
Section: Introductionmentioning
confidence: 90%
“…The population frequency of ABCA4 alleles is high—1:20 people carry a potentially pathogenic ABCA4 allele 7 9. Therefore, recent efforts have been directed towards two goals; first, to find the missing ABCA4 disease-causing alleles in non-coding sequences8 and, second, to perform extensive whole exome sequencing (WES) in patients with 0 ABCA4 alleles (and ABCA4-like phenotypes) to differentiate non- ABCA4 phenocopies 10–13. Substantial progress has been made with respect to both objectives: several deep intronic ABCA4 variants have been proven to affect splicing8 14 and preliminary data (not shown) indicate that such is also true of rare variants affecting ABCA4 expression.…”
Section: Introductionmentioning
confidence: 99%
“…b An exonic mutation in USH1C (c.216G > A) activates a new cryptic splice donor site that results in the insertion of a shorter fragment of exon 3 to USH1C mRNA, causing a frame-shift and premature termination of the harmonin protein encoded by USH1C. Administration of AONs (in green) blocks the cryptic splice donor site and restores normal USH1C splicing (Lentz et al 2013) Other deep-intronic mutations underlying IRD and that could be treated in a similar way include those in ABCA4 (Braun et al 2013;Zernant et al 2014), CHM (van den Hurk et al 2003), OFD1 (Webb et al 2012) and USH2A (Vache et al 2012). Alternatively, AONs can be employed to skip (combinations of) exons that contain nonsense or frame-shift mutations, taking into account to leave the reading-frame intact, or to restore the reading-frame in case this is disrupted by large deletions encompassing one or more exons.…”
Section: Aon-based Therapy For Inherited Retinal Degenerationsmentioning
confidence: 99%
“…16 In carriers of monoallelic ABCA4 variants, the second variant can reside in introns, outside of splice sites, not detected by standard sequencing methods. [17][18][19][20] A very small fraction of these unidentified defects comprise copy number variants that elude detection by PCR-based sequencing techniques. 18,[21][22][23] Identification of disease-causing alleles and insight into their associations with differences in disease presentation and severity are essential for the counseling of patients and become increasingly important, as research on therapeutic approaches is rapidly evolving.…”
mentioning
confidence: 99%