{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T10:43:57Z","timestamp":1788173037528,"version":"build-2803163510"},"reference-count":38,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,17]],"date-time":"2023-01-17T00:00:00Z","timestamp":1673913600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Neuronal ceroid lipofuscinoses (CNL) are lysosomal storage diseases that represent the most common cause of dementia in children. To date, 13 autosomal recessive (AR) and 1 autosomal dominant (AD) gene have been characterized. Biallelic variants in MFSD8 cause CLN7 type, with nearly 50 pathogenic variants, mainly truncating and missense, reported so far. Splice site variants require functional validation. We detected a novel homozygous non-canonical splice-site variant in MFSD8 in a 5-year-old girl who presented with progressive neurocognitive impairment and microcephaly. The diagnostic procedure was elicited by clinical genetics first, and then confirmed by cDNA sequencing and brain imaging. Inferred by the common geographic origin of the parents, an autosomal recessive inheritance was hypothesized, and SNP-array was performed as the first-line genetic test. Only three AR genes lying within the observed 24 Mb regions of homozygosity were consistent with the clinical phenotype, including EXOSC9, SPATA5 and MFSD8. The cerebral and cerebellar atrophy detected in the meantime by MRI, along with the suspicion of accumulation of ceroid lipopigment in neurons, prompted us to perform targeted MFSD8 sequencing. Following the detection of a splice site variant of uncertain significance, skipping of exon 8 was demonstrated by cDNA sequencing, and the variant was redefined as pathogenic.<\/jats:p>","DOI":"10.3390\/genes14020245","type":"journal-article","created":{"date-parts":[[2023,1,18]],"date-time":"2023-01-18T01:57:57Z","timestamp":1674007077000},"page":"245","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Linear Diagnostic Procedure Elicited by Clinical Genetics and Validated by mRNA Analysis in Neuronal Ceroid Lipofuscinosis 7 Associated with a Novel Non-Canonical Splice Site Variant in MFSD8"],"prefix":"10.3390","volume":"14","author":[{"given":"Domizia","family":"Pasquetti","sequence":"first","affiliation":[{"name":"Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6898-8882","authenticated-orcid":false,"given":"Giuseppe","family":"Marangi","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Orteschi","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3066-5348","authenticated-orcid":false,"given":"Marina","family":"Carapelle","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica Francesca","family":"L\u2019Erario","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romina","family":"Venditti","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Department of Neuroscience, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Maietta","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenica Immacolata","family":"Battaglia","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Department of Neuroscience, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Contaldo","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Department of Neuroscience, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2267-8077","authenticated-orcid":false,"given":"Chiara","family":"Veredice","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Department of Neuroscience, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4871-9519","authenticated-orcid":false,"given":"Marcella","family":"Zollino","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1016\/j.bbadis.2012.08.012","article-title":"The Neuronal Ceroid-Lipofuscinoses: A Historical Introduction","volume":"1832","author":"Haltia","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2256","DOI":"10.1016\/j.bbadis.2015.05.014","article-title":"Towards a New Understanding of NCL Pathogenesis","volume":"1852","author":"Cooper","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.1016\/j.bbadis.2015.05.007","article-title":"Human NCL Neuropathology","volume":"1852","author":"Radke","year":"2015","journal-title":"Biochim. Biophys. Acta BBA Mol. 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