2017
DOI: 10.1167/iovs.16-19936
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Mutation Spectrum of the ABCA4 Gene in 335 Stargardt Disease Patients From a Multicenter German Cohort—Impact of Selected Deep Intronic Variants and Common SNPs

Abstract: PurposeStargardt disease (STGD1) is an autosomal recessive retinopathy, caused by mutations in the retina-specific ATP-binding cassette transporter (ABCA4) gene. To establish the mutational spectrum and to assess effects of selected deep intronic and common genetic variants on disease, we performed a comprehensive sequence analysis in a large cohort of German STGD1 patients.MethodsDNA samples of 335 STGD1 patients were analyzed for ABCA4 mutations in its 50 coding exons and adjacent intronic sequences by reseq… Show more

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Cited by 115 publications
(115 citation statements)
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“…The other novel variant c.3191–19G>A, tested in BA16, did not show a splice defect (Figure S3). In addition to this novel splice variant, the previously reported variant c.6148G>C (Schulz et al, ) did not show a splice defect using BA31 (Figure S3).…”
Section: Resultsmentioning
confidence: 99%
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“…The other novel variant c.3191–19G>A, tested in BA16, did not show a splice defect (Figure S3). In addition to this novel splice variant, the previously reported variant c.6148G>C (Schulz et al, ) did not show a splice defect using BA31 (Figure S3).…”
Section: Resultsmentioning
confidence: 99%
“…First, variants were prioritized by using the criteria “Quality by Depth” >500, which represents the overall coverage of the region, an Allele frequency (AF) < 0.005 in the dbSNP database and in an in‐house whole exome data set of 21,559 persons, and an AF < 0.01 in control population datasets, such as the Genome Aggregation Database (gnomAD; http://gnomad.broadinstitute.org/), and passing standard quality filters including gene components such as exons and canonical splice sites were prioritized. Previously reported pathogenic variants with high AFs such as c.2588G>C and c.5603A>T (AFs in non‐Finnish European [nFE] in gnomAD 0.00784 and 0.06647, respectively) (Cornelis et al, ; F. P. Cremers et al, ; Schulz et al, ; Zernant et al, , ), were selected separately. Known deep‐intronic variants were selected based on prior knowledge from literature (Albert et al, ; Bauwens et al, , ; Braun et al, ; Sangermano et al, ; Schulz et al, ; Zernant et al, ).…”
Section: Methodsmentioning
confidence: 99%
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“…25,26 This variant was found to be phenotypically expressed only when in trans with a deleterious mutation (i.e., presence of the variants on different alleles) and explained >50% of all monoallelic cases and~80% of late-onset cases in a US cohort. 26 In addition, the c.2588G>C (p.[Gly863Ala, Gly863del]) variant was proposed to act as a mild pathogenic variant only when in cis with p.Asn1868Ile (i.e., presence of the variants on the same allele).…”
mentioning
confidence: 99%
“…At least two pathogenic or likely pathogenic ABCA4 mutations were identified in three STGD1 patients (23%), one pathogenic or likely pathogenic ABCA4 mutation in combination with a variant of unknown significance was found in seven STGD1 patients (54%), and two variants of unknown significance were detected in one STGD1 patient (8%) whereas only one likely pathogenic ABCA4 mutation was found in two STGD1 patients (15%) (Supplementary Table S1). The frequent c.5603A>T (p.Asn1868Ile) variant recently shown to be associated with STGD1 development, in particular with the late-onset phenotype, 50,51 was identified in six STGD1 patients. Eleven STGD1 eyes and eight AMD eyes revealed foveal involvement of the RPE atrophy.…”
Section: Discussionmentioning
confidence: 96%