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There is a great genetic heterogeneity causing <jats:styled-content style=\"fixed-case\">IRD<\/jats:styled-content>s, and to date, more than 260 genes are associated with <jats:styled-content style=\"fixed-case\">IRD<\/jats:styled-content>s. Stargardt disease, type 1 (STGD1) or macular degeneration with flecks, STGD1 represents a disease with early onset, central visual impairment, frequent appearance of yellowish flecks and mutations in the ATP\u2010binding cassette subfamily A, member 4 (<jats:italic><jats:styled-content style=\"fixed-case\">ABCA4<\/jats:styled-content><\/jats:italic>) gene. A large number of intronic sequence variants in <jats:italic><jats:styled-content style=\"fixed-case\">ABCA<\/jats:styled-content>4<\/jats:italic> have been considered pathogenic although their functional effect was seldom demonstrated. In this study, we aimed to reveal how intronic variants present in patients with Stargardt from the same Swedish family affect splicing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The splicing of the <jats:italic><jats:styled-content style=\"fixed-case\">ABCA<\/jats:styled-content>4<\/jats:italic> gene was studied in human embryonic kidney cells, <jats:styled-content style=\"fixed-case\">HEK<\/jats:styled-content>293T, and in human retinal pigment epithelium cells, <jats:styled-content style=\"fixed-case\">ARPE<\/jats:styled-content>\u201019, using a minigene system containing variants c.4773+3A&gt;G and c.5461\u201010T&gt;C.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We showed that both <jats:italic><jats:styled-content style=\"fixed-case\">ABCA<\/jats:styled-content>4<\/jats:italic> variants, c.4773+3A&gt;G and c.5461\u201010T&gt;C, cause aberrant splicing of the <jats:italic><jats:styled-content style=\"fixed-case\">ABCA<\/jats:styled-content>4<\/jats:italic> minigene resulting in exon skipping. We also demonstrated that splicing of <jats:italic><jats:styled-content style=\"fixed-case\">ABCA<\/jats:styled-content>4<\/jats:italic> has different outcomes depending on transfected cell type.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Two intronic variants c.4773+3A&gt;G and c.5461\u201010T&gt;C, both predicted to affect splicing, are indeed disease\u2010causing mutations due to skipping of exons 33, 34, 39 and 40 of <jats:italic><jats:styled-content style=\"fixed-case\">ABCA<\/jats:styled-content>4<\/jats:italic> gene. The experimental proof that <jats:italic><jats:styled-content style=\"fixed-case\">ABCA<\/jats:styled-content>4<\/jats:italic> mutations in <jats:styled-content style=\"fixed-case\">STGD<\/jats:styled-content> patients affect protein function is crucial for their inclusion\u00a0to\u00a0future clinical trials; therefore, functional testing of all <jats:italic><jats:styled-content style=\"fixed-case\">ABCA<\/jats:styled-content>4<\/jats:italic> intronic variants associated with Stargardt disease by minigene technology is desirable.<\/jats:p><\/jats:sec>","DOI":"10.1111\/aos.13676","type":"journal-article","created":{"date-parts":[[2018,2,21]],"date-time":"2018-02-21T19:48:47Z","timestamp":1519242527000},"page":"737-743","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["ATP\u2010binding cassette subfamily A, member 4 intronic variants c.4773+3A&gt;G and c.5461\u201010T&gt;C cause Stargardt disease due to defective 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