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Open AccessArticle

Prevalence of ABCA4 Deep-Intronic Variants and Related Phenotype in An Unsolved “One-Hit” Cohort with Stargardt Disease

Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012 Paris, France
Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 1423, F-75012 Paris, France
Univ Lille, Inserm UMR-S 1172, CHU Lille, Biochemistry and Molecular Biology Department-UF Génopathies, F-59000 Lille, France
Fondation Ophtalmologique Adolphe de Rothschild, F-75019 Paris, France
Académie des Sciences-Institut de France, F-75006 Paris, France
Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburg, PA 15213, USA
Institute of Ophthalmology, University College of London, London EC1V 9EL, UK
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(20), 5053;
Received: 14 August 2019 / Revised: 24 September 2019 / Accepted: 9 October 2019 / Published: 11 October 2019
We investigated the prevalence of reported deep-intronic variants in a French cohort of 70 patients with Stargardt disease harboring a monoallelic pathogenic variant on the exonic regions of ABCA4. Direct Sanger sequencing of selected intronic regions of ABCA4 was conducted. Complete phenotypic analysis and correlation with the genotype was performed in case a known intronic pathogenic variant was identified. All other variants found on the analyzed sequences were queried for minor allele frequency and possible pathogenicity by in silico predictions. The second mutated allele was found in 14 (20%) subjects. The three known deep-intronic variants found were c.5196+1137G>A in intron 36 (6 subjects), c.4539+2064C>T in intron 30 (4 subjects) and c.4253+43G>A in intron 28 (4 subjects). Even though the phenotype depends on the compound effect of the biallelic variants, a genotype-phenotype correlation suggests that the c.5196+1137G>A was mostly associated with a mild phenotype and the c.4539+2064C>T with a more severe one. A variable effect was instead associated with the variant c.4253+43G>A. In addition, two novel variants, c.768+508A>G and c.859-245_859-243delinsTGA never associated with Stargardt disease before, were identified and a possible splice defect was predicted in silico. Our study calls for a larger cohort analysis including targeted locus sequencing and 3D protein modeling to better understand phenotype-genotype correlations associated with deep-intronic changes and patients’ selection for clinical trials. View Full-Text
Keywords: ABCA4; Stargardt disease; deep-intronic variants; genotype-phenotype correlation ABCA4; Stargardt disease; deep-intronic variants; genotype-phenotype correlation
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Nassisi, M.; Mohand-Saïd, S.; Andrieu, C.; Antonio, A.; Condroyer, C.; Méjécase, C.; Varin, J.; Wohlschlegel, J.; Dhaenens, C.-M.; Sahel, J.-A.; Zeitz, C.; Audo, I. Prevalence of ABCA4 Deep-Intronic Variants and Related Phenotype in An Unsolved “One-Hit” Cohort with Stargardt Disease. Int. J. Mol. Sci. 2019, 20, 5053.

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