Author Response: Penetrance of the<i>ABCA4</i>p.Asn1868Ile Allele in Stargardt Disease

Cremers, Frans P.M.; Cornelis, Stéphanie S.; Runhart, Esmee H.; Astuti, Galuh D.N.

doi:10.1167/iovs.18-25944

Cited by 19 publications

(42 citation statements)

References 11 publications

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“…A common c.5603A>T (p.Asn1868Ile) variant, strongly associated with late‐onset STGD1 (F. P. M. Cremers et al, ; Runhart et al, ; Zernant et al, ), was found in a heterozygous manner as a single variant in 144 STGD1 cases. It was previously shown that p.Asn1868Ile contributes to the pathogenicity of variants c.769–784C>T and c.2588G>C, which was consistently found in cis in patients and much less frequent in healthy persons (Sangermano et al, ; Zernant et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Disease-associated ABCA4 alleles in 411 STGD1 persons Two or more pathogenic or likely pathogenic variants in ABCA4were found in 155 of 411 STGD1 cases, 97 (24%) of whom were considered solved as they carried two (likely) pathogenic variants. Another 58 (14%) cases were considered possibly solved as they carry c.5603A>T (p.Asn1868Ile), a frequent mild but low-penetrant variant (F. P. M Cremers, Cornelis, Runhart, & Astuti, 2018;Runhart et al, 2018;Zernant et al, 2017). in trans with a moderate or severe coding or deep-intronic variant.…”

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

et al. 2019

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Purpose Stargardt disease (STGD1) is caused by biallelic mutations in ABCA4, but many patients are genetically unsolved due to insensitive mutation‐scanning methods. We aimed to develop a cost‐effective sequencing method for ABCA4 exons and regions carrying known causal deep‐intronic variants. Methods Fifty exons and 12 regions containing 14 deep‐intronic variants of ABCA4 were sequenced using double‐tiled single molecule Molecular Inversion Probe (smMIP)‐based next‐generation sequencing. DNAs of 16 STGD1 cases carrying 29 ABCA4 alleles and of four healthy persons were sequenced using 483 smMIPs. Thereafter, DNAs of 411 STGD1 cases with one or no ABCA4 variant were sequenced. The effect of novel noncoding variants on splicing was analyzed using in vitro splice assays. Results Thirty‐four ABCA4 variants previously identified in 16 STGD1 cases were reliably identified. In 155/411 probands (38%), two causal variants were identified. We identified 11 deep‐intronic variants present in 62 alleles. Two known and two new noncanonical splice site variants showed splice defects, and one novel deep‐intronic variant (c.4539+2065C>G) resulted in a 170‐nt mRNA pseudoexon insertion (p.[Arg1514Lysfs*35,=]). Conclusions smMIPs‐based sequence analysis of coding and selected noncoding regions of ABCA4 enabled cost‐effective mutation detection in STGD1 cases in previously unsolved cases.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

et al. 2019

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“…Possible reasons for these results are as follows: (1) targeted exome sequencing and WES cannot detect gross deletions, gross insertions, or complex rearrangement variants (Broadgate, Yu, Downes, & Halford, 2017), which might have been present in these families; (2) the sequence depth and coverage in this study was insufficient to call all variants accurately; (3) novel STGD-associated genes may have been filtered out during our raw data analysis; (4) deep-intronic variants in ABCA4 that are potentially associated with autosomal recessive STGD could not be captured through targeted exome sequencing and WES (Albert et al, 2018;Bauwens et al, 2015Bauwens et al, , 2019Bax et al, 2015;Braun et al, 2013;Sangermano et al, 2014;Zernant et al, 2014); and (5) diseasecausing variants with high minor allele frequency, which had not been reported previously may have been filtered out, for example, c.5603A > T, p.(Asn1868Ile) (Cremers, Cornelis, Runhart, & Astuti, 2018;Runhart et al, 2018;Zernant et al, 2017). Possible reasons for these results are as follows: (1) targeted exome sequencing and WES cannot detect gross deletions, gross insertions, or complex rearrangement variants (Broadgate, Yu, Downes, & Halford, 2017), which might have been present in these families; (2) the sequence depth and coverage in this study was insufficient to call all variants accurately; (3) novel STGD-associated genes may have been filtered out during our raw data analysis; (4) deep-intronic variants in ABCA4 that are potentially associated with autosomal recessive STGD could not be captured through targeted exome sequencing and WES (Albert et al, 2018;Bauwens et al, 2015Bauwens et al, , 2019Bax et al, 2015;Braun et al, 2013;Sangermano et al, 2014;Zernant et al, 2014); and (5) diseasecausing variants with high minor allele frequency, which had not been reported previously may have been filtered out, for example, c.5603A > T, p.(Asn1868Ile) (Cremers, Cornelis, Runhart, & Astuti, 2018;Runhart et al, 2018;Zernant et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we did not detect a disease-causing variant in three families (25.00%), and we detected only one heterozygous variant in the ABCA4 gene in one family (8.33%). Possible reasons for these results are as follows: (1) targeted exome sequencing and WES cannot detect gross deletions, gross insertions, or complex rearrangement variants (Broadgate, Yu, Downes, & Halford, 2017), which might have been present in these families; (2) the sequence depth and coverage in this study was insufficient to call all variants accurately; (3) novel STGD-associated genes may have been filtered out during our raw data analysis; (4) deep-intronic variants in ABCA4 that are potentially associated with autosomal recessive STGD could not be captured through targeted exome sequencing and WES (Albert et al, 2018;Bauwens et al, 2015Bauwens et al, , 2019Bax et al, 2015;Braun et al, 2013;Sangermano et al, 2014;Zernant et al, 2014); and (5) diseasecausing variants with high minor allele frequency, which had not been reported previously may have been filtered out, for example, c.5603A > T, p.(Asn1868Ile) (Cremers, Cornelis, Runhart, & Astuti, 2018;Runhart et al, 2018;Zernant et al, 2017). Whole-genome sequencing (WGS) may be a useful alternative strategy to resolve these problems (Carrigan et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Application of targeted exome and whole‐exome sequencing for Chinese families with Stargardt disease

Dan

Huang

Xing

et al. 2019

Annals of Human Genetics

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Objective: The aim of this study was to investigate pathogenic variants and molecular etiologies of Stargardt disease (STGD) in a cohort of Chinese families. Materials and Methods:A cohort of 12 unrelated STGD families diagnosed on the basis of clinical manifestations underwent analysis by targeted exome or whole-exome sequencing. Bioinformatics analysis, Sanger sequencing, and cosegregation analysis of available family members were used to validate sequencing data and confirm the presence of disease-causing genes.Results: Using targeted exome and whole-exome sequencing, we found that eight families had disease-causing variants in the ABCA4 gene, one family had only one heterozygous variant in the ABCA4 gene, and the remaining three families have not been identified with any disease-causing variants for STGD. We identified 15 variants in the ABCA4 gene; of these, five variants have not been previously described for STGD. Conclusion:The findings in this study expand the data regarding the frequency and spectrum of variants in the ABCA4 gene, thus potentially enriching our understanding of the molecular basis of STGD. Moreover, they constitute clues for future STGD diagnosis and therapy.

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“…STGD1 is the most frequent inherited macular dystrophy with an estimated prevalence of 1/10,000 (Blacharski et al 1988). Different combinations of variants result in a spectrum of clinical phenotypes, ranging from i) pan-retinal dystrophy with an early age at onset due to two severe or null variants, to ii) adolescent or young adult-onset disease observed in probands with typical STGD1 due to the combined effect of a severe and a mild variant, and iii) late-onset STGD1 often due to a severe variant combined with a mild/hypomorphic variant, one of which (p.Asn1868Ile) displays reduced penetrance (Allikmets et al 1997;Cremers et al 1998;Westeneng-van Haaften et al 2012;Zernant et al 2017;Cremers et al 2018;Runhart et al 2018). Thus far, 1,180 unique ABCA4 variants have been reported in 8,777 alleles of 6,684 cases (Cornelis et al 2017) (www.lovd.nl/ABCA4).…”

Section: Introductionmentioning

confidence: 99%

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

Khan¹,

Cornelis²,

Pozo‐Valero³

et al. 2019

Preprint

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Missing 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.

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Author Response: Penetrance of theABCA4p.Asn1868Ile Allele in Stargardt Disease

Cited by 19 publications

References 11 publications

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

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

Application of targeted exome and whole‐exome sequencing for Chinese families with Stargardt disease

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

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