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

Authors :
Runhart EH
Valkenburg D
Cornelis SS
Khan M
Sangermano R
Albert S
Bax NM
Astuti GDN
Gilissen C
Pott JR
Verheij JBGM
Blokland EAW
Cremers FPM
van den Born LI
Hoyng CB
Source :
Investigative ophthalmology & visual science [Invest Ophthalmol Vis Sci] 2019 Oct 01; Vol. 60 (13), pp. 4249-4256.
Publication Year :
2019

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).<br />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.[769-784C>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).<br />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., ∼30% of the c.769-784C>T allele alone).<br />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.

Details

Language :
English
ISSN :
1552-5783
Volume :
60
Issue :
13
Database :
MEDLINE
Journal :
Investigative ophthalmology & visual science
Publication Type :
Academic Journal
Accession number :
31618761
Full Text :
https://doi.org/10.1167/iovs.19-27524