The Common<i>ABCA4</i>Variant p.Asn1868Ile Shows Nonpenetrance and Variable Expression of Stargardt Disease When Present in<i>trans</i>With Severe Variants

Runhart, Esmee H.; Sangermano, Riccardo; Cornelis, Stéphanie S.; Verheij, Joanne; Plomp, Astrid S.; Boon, Camiel J F; Lugtenberg, Dorien; Roosing, Susanne; Bax, Nathalie M.; Blokland, Ellen A.W.; Jacobs-Camps, Marlie H M; Velde-Visser, S.D. van der; Pott, Jan-Willem R.; Rohrschneider, Klaus; Thiadens, Alberta A H J; Klaver, Caroline C W; Born, L. Ingeborgh van den; Hoyng, Carel B.; Cremers, Frans P.M.

doi:10.1167/iovs.18-23881

Cited by 69 publications

(125 citation statements)

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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%

“…Until recently, 35% of STGD1 cases carried one or no coding or splice site mutation (Zernant et al, ). Copy‐number variations (CNVs), deep‐intronic variants (Bauwens et al, ; Bax et al, ; Braun et al, ; Zernant et al, ), and a low‐penetrant frequent coding variant (p.Asn1868Ile) (Runhart et al, ; Zernant et al, ) explained about 10% of this missing heritability. Recently, upon sequence analysis of the entire ABCA4 gene, eight novel and one known deep‐intronic variant explained approximately 65% of the remaining unsolved cases (Bauwens et al, ; Sangermano et al, ; Zernant et al, ).…”

Section: Introductionmentioning

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%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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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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“…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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Association of Sex With Frequent and Mild ABCA4 Alleles in Stargardt Disease

et al. 2020

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IMPORTANCEThe mechanisms behind the phenotypic variability and reduced penetrance in autosomal recessive Stargardt disease (STGD1), often a blinding disease, are poorly understood. Identification of the unknown disease modifiers can improve patient and family counseling and provide valuable information for disease management.OBJECTIVE To assess the association of incompletely penetrant ABCA4 alleles with sex in STGD1.DESIGN, SETTING, AND PARTICIPANTS Genetic data for this cross-sectional study were obtained from 2 multicenter genetic studies of 1162 patients with clinically suspected STGD1. Unrelated patients with genetically confirmed STGD1 were selected. The data were collected from June 2016 to June 2019, and post hoc analysis was performed between July 2019 and January 2020.MAIN OUTCOMES AND MEASURES Penetrance of reported mild ABCA4 variants was calculated by comparing the allele frequencies in the general population (obtained from the Genome Aggregation Database) with the genotyping data in the patient population (obtained from the ABCA4 Leiden Open Variation Database). The sex ratio among patients with and patients without an ABCA4 allele with incomplete penetrance was assessed.RESULTS A total of 550 patients were included in the study, among which the mean (SD) age was 45.7 (18.0) years and most patients were women (311 [57%]). Five of the 5 mild ABCA4 alleles, including c.5603A>T and c.5882G>A, were calculated to have incomplete penetrance. The women to men ratio in the subgroup carrying c.5603A>T was 1.7 to 1; the proportion of women in this group was higher compared with the subgroup not carrying a mild allele (difference, 13%; 95% CI, 3%-23%; P = .02). The women to men ratio in the c.5882G>A subgroup was 2.1 to 1, and the women were overrepresented compared with the group carrying no mild allele (difference, 18%; 95% CI, 6%-30%; P = .005).CONCLUSIONS AND RELEVANCE This study found an imbalance in observed sex ratio among patients harboring a mild ABCA4 allele, which concerns approximately 25% of all patients with STGD1, suggesting that STGD1 should be considered a polygenic or multifactorial disease rather than a disease caused by ABCA4 gene mutations alone. The findings suggest that sex should be considered as a potential disease-modifying variable in both basic research and clinical trials on STGD1.

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The CommonABCA4Variant p.Asn1868Ile Shows Nonpenetrance and Variable Expression of Stargardt Disease When Present intransWith Severe Variants

Cited by 69 publications

References 35 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

Association of Sex With Frequent and Mild ABCA4 Alleles in Stargardt Disease

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