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Here, we functionally characterized two novel <jats:italic>MFSD8<\/jats:italic> variants found in a child with juvenile isolated maculopathy, in order to establish a refined prognosis. <jats:italic>ABCA4<\/jats:italic> locus resequencing was followed by the analysis of other inherited retinal disease genes by whole exome sequencing (WES). Minigene assays and cDNA sequencing were used to assess the effect of a novel <jats:italic>MFSD8<\/jats:italic> splice variant. <jats:italic>MFSD8<\/jats:italic> expression was quantified with qPCR and overexpression studies were analyzed by immunoblotting. Transmission electron microscopy (TEM) was performed on a skin biopsy and ophthalmological and neurological re\u2010examinations were conducted. WES revealed two novel <jats:italic>MFSD8<\/jats:italic> variants: c.[590del];[439+3A&gt;C] p.[Gly197Valfs*2];[Ile67Glufs*3]. Characterization of the c.439+3A&gt;C variant via splice assays showed exon\u2010skipping (p.Ile67Glufs*3), while overexpression studies of the corresponding protein indicated expression of a truncated polypeptide. In addition, a significantly reduced <jats:italic>MFSD8<\/jats:italic> RNA expression was noted in patient's lymphocytes. TEM of a skin biopsy revealed typical v\u2010LINCL lipopigment inclusions while neurological imaging of the proband displayed subtle cerebellar atrophy. Functional characterization demonstrated the pathogenicity of two novel <jats:italic>MFSD8<\/jats:italic> variants, found in a child with an initial diagnosis of juvenile isolated maculopathy but likely evolving to v\u2010LINCL with a protracted disease course. Our study allowed a refined neurological prognosis in the proband and expands the natural history of <jats:italic>MFSD8<\/jats:italic>\u2010associated disease.<\/jats:p>","DOI":"10.1111\/cge.13673","type":"journal-article","created":{"date-parts":[[2019,11,13]],"date-time":"2019-11-13T16:13:25Z","timestamp":1573661605000},"page":"426-436","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Functional characterization of novel <i>MFSD8<\/i> pathogenic variants anticipates neurological involvement in juvenile isolated maculopathy"],"prefix":"10.1111","volume":"97","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0402-9006","authenticated-orcid":false,"given":"Miriam","family":"Bauwens","sequence":"first","affiliation":[{"name":"Center for Medical Genetics Ghent University  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Storch","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Children's Hospital University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Weisschuh","sequence":"additional","affiliation":[{"name":"Molecular Genetics Laboratory, Institute for Ophthalmic Research University of Tuebingen  Tuebingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantal","family":"Ceuterick\u2010de Groote","sequence":"additional","affiliation":[{"name":"Laboratory of Neuromuscular Pathology Institute Born\u2010Bunge (IBB) and University of Antwerp  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riet","family":"De Rycke","sequence":"additional","affiliation":[{"name":"Department of Biomedical Molecular Biology Ghent University  Ghent Belgium"},{"name":"VIB\u2010UGent Center for Inflammation Research  Ghent Belgium"},{"name":"Ghent University Expertise Centre for Transmission Electron Microscopy and VIB BioImaging Core  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brecht","family":"Guillemyn","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Ghent University  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"De Jaegere","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Ghent University Hospital  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frauke","family":"Coppieters","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Ghent University Hospital  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudy","family":"Van Coster","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Neurology and Metabolism Ghent University Hospital  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart P.","family":"Leroy","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Ghent University Hospital  Ghent Belgium"},{"name":"Department of Ophthalmology Ghent University and Ghent University Hospital  Ghent Belgium"},{"name":"Division of Ophthalmology and Center for Cellular &amp; Molecular Therapeutics The Children's Hospital of Philadelphia  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elfride","family":"De Baere","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Ghent University  Ghent Belgium"},{"name":"Center for Medical Genetics Ghent University Hospital  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,12,12]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2014.07.040"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.16-20608"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0207958"},{"issue":"0","key":"e_1_2_8_5_1","first-page":"1","article-title":"MFSD8 gene mutations; evidence for phenotypic heterogeneity","volume":"0","author":"Zare\u2010Abdollahi D","year":"2019","journal-title":"Ophthal Genet"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1086\/518902"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20975"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-009-0185-1"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21624"},{"key":"e_1_2_8_10_1","first-page":"2301","article-title":"The neuronal ceroid lipofuscinoses program: a translational research experience in Argentina. 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