Publication

Late-Onset Stargardt Disease Due to Mild, Deep-Intronic ABCA4 Alleles

Runhart, E. H., Valkenburg, D., Cornelis, S. S., Khan, M., Sangermano, R., Albert, S., Bax, N. M., Astuti, G. D. N., Gilissen, C., Pott, J-W. R., Verheij, J. B. G. M., Blokland, E. A. W., Cremers, F. P. M., van den Born, L. I. & Hoyng, C. B., Oct-2019, In : Investigative ophthalmology & visual science. 60, 13, p. 4249-4256 8 p.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Runhart, E. H., Valkenburg, D., Cornelis, S. S., Khan, M., Sangermano, R., Albert, S., ... Hoyng, C. B. (2019). Late-Onset Stargardt Disease Due to Mild, Deep-Intronic ABCA4 Alleles. Investigative ophthalmology & visual science, 60(13), 4249-4256. https://doi.org/10.1167/iovs.19-27524

Author

Runhart, Esmee H. ; Valkenburg, Dyon ; Cornelis, Stephanie S. ; Khan, Mubeen ; Sangermano, Riccardo ; Albert, Silvia ; Bax, Nathalie M. ; Astuti, Galuh D. N. ; Gilissen, Christian ; Pott, Jan-Willem R. ; Verheij, Joke B. G. M. ; Blokland, Ellen A. W. ; Cremers, Frans P. M. ; van den Born, L. Ingeborgh ; Hoyng, Carel B. / Late-Onset Stargardt Disease Due to Mild, Deep-Intronic ABCA4 Alleles. In: Investigative ophthalmology & visual science. 2019 ; Vol. 60, No. 13. pp. 4249-4256.

Harvard

Runhart, EH, Valkenburg, D, Cornelis, SS, Khan, M, Sangermano, R, Albert, S, Bax, NM, Astuti, GDN, Gilissen, C, Pott, J-WR, Verheij, JBGM, Blokland, EAW, Cremers, FPM, van den Born, LI & Hoyng, CB 2019, 'Late-Onset Stargardt Disease Due to Mild, Deep-Intronic ABCA4 Alleles', Investigative ophthalmology & visual science, vol. 60, no. 13, pp. 4249-4256. https://doi.org/10.1167/iovs.19-27524

Standard

Late-Onset Stargardt Disease Due to Mild, Deep-Intronic ABCA4 Alleles. / Runhart, Esmee H.; Valkenburg, Dyon; Cornelis, Stephanie S.; Khan, Mubeen; Sangermano, Riccardo; Albert, Silvia; Bax, Nathalie M.; Astuti, Galuh D. N.; Gilissen, Christian; Pott, Jan-Willem R.; Verheij, Joke B. G. M.; Blokland, Ellen A. W.; Cremers, Frans P. M.; van den Born, L. Ingeborgh; Hoyng, Carel B.

In: Investigative ophthalmology & visual science, Vol. 60, No. 13, 10.2019, p. 4249-4256.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Runhart EH, Valkenburg D, Cornelis SS, Khan M, Sangermano R, Albert S et al. Late-Onset Stargardt Disease Due to Mild, Deep-Intronic ABCA4 Alleles. Investigative ophthalmology & visual science. 2019 Oct;60(13):4249-4256. https://doi.org/10.1167/iovs.19-27524


BibTeX

@article{cd3c02c039e743fbb30a8a48fdecccec,
title = "Late-Onset Stargardt Disease Due to Mild, Deep-Intronic ABCA4 Alleles",
abstract = "PURPOSE. To investigate the role of two deep-intronic ABCA4 variants, that showed a mild splice defect in vitro and can occur on the same allele as the low penetrant c.5603A>T, in Stargardt disease (STGD1).METHODS. Ophthalmic data were assessed of 18 STGD1 patients who harbored c.769-784C>T or c.4253+43G>A in combination with a severe ABCA4 variant. Subjects carrying c.[769784C>T; 5603A>T] were clinically compared with a STGD1 cohort previously published carrying c.5603A>T noncomplex. We calculated the penetrances of the intronic variants using ABCA4 allele frequency data of the general population and investigated the effect of c.769-784C>T on splicing in photoreceptor progenitor cells (PPCs).RESULTS. Mostly, late-onset, foveal-sparing STGD1 was observed among subjects harboring c.769-784C>T or c.4253+43G>A (median age of onset, 54.5 and 52.0 years, respectively). However, ages of onset, phenotypes in fundo, and visual acuity courses varied widely. No significant clinical differences were observed between the c.[769-784C>T; 5603A>T] cohort and the c.4253+43G>A or the c.5603A>T cohort. The penetrances of c.769-784C>T (20.5{\%}-39.6{\%}) and c.4253+43G>A (35.8{\%}-43.1{\%}) were reduced, when not considering the effect of yet unidentified or known factors in cis, such as c.5603A>T (identified in 7/7 probands with c.769-784C>T; 1/8 probands with c.4253+43G>A). Variant c.769-784C>T resulted in a pseudo-exon insertion in 15{\%} of the total mRNA (i.e., similar to 30{\%} of the c.769-784C>T allele alone).CONCLUSIONS. Two mild intronic ABCA4 variants could further explain missing heritability in late-onset STGD1, distinguishing it from AMD. The observed clinical variability and calculated reduced penetrance urge research into modifiers within and outside of the ABCA4 gene.",
keywords = "Stargardt disease, ABCA4, disease expression, penetrance, differential diagnosis, RETINAL-PIGMENT EPITHELIUM, P.ASN1868ILE ALLELE, MOUSE MODEL, AUTOFLUORESCENCE, NONPENETRANCE, PENETRANCE",
author = "Runhart, {Esmee H.} and Dyon Valkenburg and Cornelis, {Stephanie S.} and Mubeen Khan and Riccardo Sangermano and Silvia Albert and Bax, {Nathalie M.} and Astuti, {Galuh D. N.} and Christian Gilissen and Pott, {Jan-Willem R.} and Verheij, {Joke B. G. M.} and Blokland, {Ellen A. W.} and Cremers, {Frans P. M.} and {van den Born}, {L. Ingeborgh} and Hoyng, {Carel B.}",
year = "2019",
month = "10",
doi = "10.1167/iovs.19-27524",
language = "English",
volume = "60",
pages = "4249--4256",
journal = "Investigative ophthalmology & visual science",
issn = "0146-0404",
publisher = "ASSOC RESEARCH VISION OPHTHALMOLOGY INC",
number = "13",

}

RIS

TY - JOUR

T1 - Late-Onset Stargardt Disease Due to Mild, Deep-Intronic ABCA4 Alleles

AU - Runhart, Esmee H.

AU - Valkenburg, Dyon

AU - Cornelis, Stephanie S.

AU - Khan, Mubeen

AU - Sangermano, Riccardo

AU - Albert, Silvia

AU - Bax, Nathalie M.

AU - Astuti, Galuh D. N.

AU - Gilissen, Christian

AU - Pott, Jan-Willem R.

AU - Verheij, Joke B. G. M.

AU - Blokland, Ellen A. W.

AU - Cremers, Frans P. M.

AU - van den Born, L. Ingeborgh

AU - Hoyng, Carel B.

PY - 2019/10

Y1 - 2019/10

N2 - PURPOSE. To investigate the role of two deep-intronic ABCA4 variants, that showed a mild splice defect in vitro and can occur on the same allele as the low penetrant c.5603A>T, in Stargardt disease (STGD1).METHODS. Ophthalmic data were assessed of 18 STGD1 patients who harbored c.769-784C>T or c.4253+43G>A in combination with a severe ABCA4 variant. Subjects carrying c.[769784C>T; 5603A>T] were clinically compared with a STGD1 cohort previously published carrying c.5603A>T noncomplex. We calculated the penetrances of the intronic variants using ABCA4 allele frequency data of the general population and investigated the effect of c.769-784C>T on splicing in photoreceptor progenitor cells (PPCs).RESULTS. Mostly, late-onset, foveal-sparing STGD1 was observed among subjects harboring c.769-784C>T or c.4253+43G>A (median age of onset, 54.5 and 52.0 years, respectively). However, ages of onset, phenotypes in fundo, and visual acuity courses varied widely. No significant clinical differences were observed between the c.[769-784C>T; 5603A>T] cohort and the c.4253+43G>A or the c.5603A>T cohort. The penetrances of c.769-784C>T (20.5%-39.6%) and c.4253+43G>A (35.8%-43.1%) were reduced, when not considering the effect of yet unidentified or known factors in cis, such as c.5603A>T (identified in 7/7 probands with c.769-784C>T; 1/8 probands with c.4253+43G>A). Variant c.769-784C>T resulted in a pseudo-exon insertion in 15% of the total mRNA (i.e., similar to 30% of the c.769-784C>T allele alone).CONCLUSIONS. Two mild intronic ABCA4 variants could further explain missing heritability in late-onset STGD1, distinguishing it from AMD. The observed clinical variability and calculated reduced penetrance urge research into modifiers within and outside of the ABCA4 gene.

AB - PURPOSE. To investigate the role of two deep-intronic ABCA4 variants, that showed a mild splice defect in vitro and can occur on the same allele as the low penetrant c.5603A>T, in Stargardt disease (STGD1).METHODS. Ophthalmic data were assessed of 18 STGD1 patients who harbored c.769-784C>T or c.4253+43G>A in combination with a severe ABCA4 variant. Subjects carrying c.[769784C>T; 5603A>T] were clinically compared with a STGD1 cohort previously published carrying c.5603A>T noncomplex. We calculated the penetrances of the intronic variants using ABCA4 allele frequency data of the general population and investigated the effect of c.769-784C>T on splicing in photoreceptor progenitor cells (PPCs).RESULTS. Mostly, late-onset, foveal-sparing STGD1 was observed among subjects harboring c.769-784C>T or c.4253+43G>A (median age of onset, 54.5 and 52.0 years, respectively). However, ages of onset, phenotypes in fundo, and visual acuity courses varied widely. No significant clinical differences were observed between the c.[769-784C>T; 5603A>T] cohort and the c.4253+43G>A or the c.5603A>T cohort. The penetrances of c.769-784C>T (20.5%-39.6%) and c.4253+43G>A (35.8%-43.1%) were reduced, when not considering the effect of yet unidentified or known factors in cis, such as c.5603A>T (identified in 7/7 probands with c.769-784C>T; 1/8 probands with c.4253+43G>A). Variant c.769-784C>T resulted in a pseudo-exon insertion in 15% of the total mRNA (i.e., similar to 30% of the c.769-784C>T allele alone).CONCLUSIONS. Two mild intronic ABCA4 variants could further explain missing heritability in late-onset STGD1, distinguishing it from AMD. The observed clinical variability and calculated reduced penetrance urge research into modifiers within and outside of the ABCA4 gene.

KW - Stargardt disease

KW - ABCA4

KW - disease expression

KW - penetrance

KW - differential diagnosis

KW - RETINAL-PIGMENT EPITHELIUM

KW - P.ASN1868ILE ALLELE

KW - MOUSE MODEL

KW - AUTOFLUORESCENCE

KW - NONPENETRANCE

KW - PENETRANCE

U2 - 10.1167/iovs.19-27524

DO - 10.1167/iovs.19-27524

M3 - Article

VL - 60

SP - 4249

EP - 4256

JO - Investigative ophthalmology & visual science

JF - Investigative ophthalmology & visual science

SN - 0146-0404

IS - 13

ER -

ID: 101943979