{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T11:18:22Z","timestamp":1777288702900,"version":"3.51.4"},"reference-count":78,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T00:00:00Z","timestamp":1698192000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"national funds through FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia, I.P.","doi-asserted-by":"publisher","award":["EXPL\/BTM-TEC\/1477\/2021"],"award-info":[{"award-number":["EXPL\/BTM-TEC\/1477\/2021"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"national funds through FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia, I.P.","doi-asserted-by":"publisher","award":["UIDB\/00211\/2020"],"award-info":[{"award-number":["UIDB\/00211\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"national funds","award":["EXPL\/BTM-TEC\/1477\/2021"],"award-info":[{"award-number":["EXPL\/BTM-TEC\/1477\/2021"]}]},{"name":"national funds","award":["UIDB\/00211\/2020"],"award-info":[{"award-number":["UIDB\/00211\/2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Niemann\u2013Pick type C (NPC, ORPHA: 646) is a neuro-visceral, psychiatric disease caused predominantly by pathogenic variants in the NPC1 gene or seldom in NPC2. The rarity of the disease, and its wide range of clinical phenotypes and ages of onset, turn the diagnosis into a significant challenge. Other than the detailed clinical history, the typical diagnostic work-up for NPC includes the quantification of pathognomonic metabolites. However, the molecular basis diagnosis is still of utmost importance to fully characterize the disorder. Here, the authors provide an overview of splicing variants in the NPC1 and NPC2 genes and propose a new workflow for NPC diagnosis. Splicing variants cover a significant part of the disease-causing variants in NPC. The authors used cDNA analysis to study the impact of such variants, including the collection of data to classify them as leaky or non-leaky pathogenic variants. However, the presence of naturally occurring spliced transcripts can misdiagnose or mask a pathogenic variant and make the analysis even more difficult. Analysis of the NPC1 cDNA in NPC patients in parallel with controls is vital to assess and detect alternatively spliced forms. Moreover, nonsense-mediated mRNA decay (NMD) analysis plays an essential role in evaluating the naturally occurring transcripts during cDNA analysis and distinguishing them from other pathogenic variants\u2019 associated transcripts.<\/jats:p>","DOI":"10.3390\/genes14111990","type":"journal-article","created":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T04:14:47Z","timestamp":1698207287000},"page":"1990","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Challenges in the Definitive Diagnosis of Niemann\u2013Pick Type C\u2014Leaky Variants and Alternative Transcripts"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3726-2851","authenticated-orcid":false,"given":"Marisa","family":"Encarna\u00e7\u00e3o","sequence":"first","affiliation":[{"name":"Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, INSA I.P., Rua Alexandre Herculano, 321, 4000-055 Porto, Portugal"},{"name":"Center for the Study of Animal Science-Instituto de Ci\u00eancias, Tecnologias e Agroambiente da Universidade do Porto, CECA-ICETA, University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"},{"name":"Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculdade de Medicina Veterin\u00e1ria Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1067-8248","authenticated-orcid":false,"given":"Isaura","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Bioqu\u00edmica Gen\u00e9tica, Servi\u00e7o de Gen\u00e9tica Laboratorial, Centro de Gen\u00e9tica M\u00e9dica Jacinto Magalh\u00e3es, Centro Hospitalar e Universit\u00e1rio de Santo Ant\u00f3nio (CHUdSA), 4099-001 Porto, Portugal"},{"name":"UMIB-Unit for Multidisciplinary Research in Biomedicine, ICBAS, University of Porto, 4099-002 Porto, Portugal"},{"name":"ITR\u2014Laboratory for Integrative and Translational Research in Population Health, 4050-600 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9623-4017","authenticated-orcid":false,"given":"Hugo","family":"David","sequence":"additional","affiliation":[{"name":"Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, INSA I.P., Rua Alexandre Herculano, 321, 4000-055 Porto, Portugal"},{"name":"Center for the Study of Animal Science-Instituto de Ci\u00eancias, Tecnologias e Agroambiente da Universidade do Porto, CECA-ICETA, University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"},{"name":"Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculdade de Medicina Veterin\u00e1ria Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"},{"name":"Biology Department, Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2222-3622","authenticated-orcid":false,"given":"Maria Francisca","family":"Coutinho","sequence":"additional","affiliation":[{"name":"Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, INSA I.P., Rua Alexandre Herculano, 321, 4000-055 Porto, Portugal"},{"name":"Center for the Study of Animal Science-Instituto de Ci\u00eancias, Tecnologias e Agroambiente da Universidade do Porto, CECA-ICETA, University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"},{"name":"Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculdade de Medicina Veterin\u00e1ria Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"}]},{"given":"Dulce","family":"Quelhas","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Bioqu\u00edmica Gen\u00e9tica, Servi\u00e7o de Gen\u00e9tica Laboratorial, Centro de Gen\u00e9tica M\u00e9dica Jacinto Magalh\u00e3es, Centro Hospitalar e Universit\u00e1rio de Santo Ant\u00f3nio (CHUdSA), 4099-001 Porto, Portugal"},{"name":"UMIB-Unit for Multidisciplinary Research in Biomedicine, ICBAS, University of Porto, 4099-002 Porto, Portugal"},{"name":"ITR\u2014Laboratory for Integrative and Translational Research in Population Health, 4050-600 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8881-9197","authenticated-orcid":false,"given":"Sandra","family":"Alves","sequence":"additional","affiliation":[{"name":"Research and Development Unit, Department of Human Genetics, National Institute of Health Doutor Ricardo Jorge, INSA I.P., Rua Alexandre Herculano, 321, 4000-055 Porto, Portugal"},{"name":"Center for the Study of Animal Science-Instituto de Ci\u00eancias, Tecnologias e Agroambiente da Universidade do Porto, CECA-ICETA, University of Porto, Pra\u00e7a Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal"},{"name":"Associate Laboratory for Animal and Veterinary Sciences, AL4AnimalS, Faculdade de Medicina Veterin\u00e1ria Avenida da Universidade T\u00e9cnica, 1300-477 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/dmcn.13600","article-title":"Treatment Strategies for Lysosomal Storage Disorders","volume":"60","author":"Beck","year":"2018","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Encarna\u00e7\u00e3o, M., Coutinho, M.F., Silva, L., Ribeiro, D., Ouesleti, S., Campos, T., Santos, H., Martins, E., Cardoso, M.T., and Vilarinho, L. (2020). Assessing Lysosomal Disorders in the NGS Era: Identification of Novel Rare Variants. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176355"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.ymgme.2005.07.007","article-title":"Niemann-Pick C Disease: Use of Denaturing High Performance Liquid Chromatography for the Detection of NPC1 and NPC2 Genetic Variations and Impact on Management of Patients and Families","volume":"86","author":"Millat","year":"2005","journal-title":"Mol. Genet. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/gim.2015.25","article-title":"High Incidence of Unrecognized Visceral\/Neurological Late-Onset Niemann-Pick Disease, Type C1, Predicted by Analysis of Massively Parallel Sequencing Data Sets","volume":"18","author":"Wassif","year":"2016","journal-title":"Genet. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Pineda, M., Mengel, E., Jahnov\u00e1, H., H\u00e9ron, B., Imrie, J., Louren\u00e7o, C.M., van der Linden, V., Karimzadeh, P., Valayannopoulos, V., and Jesina, P. (2016). A Suspicion Index to Aid Screening of Early-Onset Niemann-Pick Disease Type C (NP-C). BMC Pediatr., 16.","DOI":"10.1186\/s12887-016-0641-7"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1212\/WNL.0b013e3182563b82","article-title":"Development of a Suspicion Index to Aid Diagnosis of Niemann-Pick Disease Type C","volume":"78","author":"Wijburg","year":"2012","journal-title":"Neurology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1002\/cyto.990080207","article-title":"Method for Detection and Isolation of Cholesteryl Ester-containing \u201cFoam\u201d Cells Using Flow Cytometry","volume":"8","author":"Kruth","year":"1987","journal-title":"Cytometry"},{"key":"ref_8","first-page":"110","article-title":"Staining of Cholesterol with the Fluorescent Antibiotic \u201cFilipin\u201d","volume":"50","author":"Boernig","year":"1974","journal-title":"Acta Histochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/bs.mcb.2014.10.028","article-title":"Laboratory Diagnosis of Niemann-Pick Disease Type C: The Filipin Staining Test","volume":"126","author":"Vanier","year":"2015","journal-title":"Methods Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6320","DOI":"10.1038\/s41598-017-06264-2","article-title":"NMR Analysis Reveals Significant Differences in the Plasma Metabolic Profiles of Niemann Pick C1 Patients, Heterozygous Carriers, and Healthy Controls","volume":"7","author":"Probert","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1194\/jlr.D015735","article-title":"A Sensitive and Specific LC-MS\/MS Method for Rapid Diagnosis of Niemann-Pick C1 Disease from Human Plasma","volume":"52","author":"Jiang","year":"2011","journal-title":"J. Lipid Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.ebiom.2015.12.018","article-title":"Rapid Diagnosis of 83 Patients with Niemann Pick Type C Disease and Related Cholesterol Transport Disorders by Cholestantriol Screening","volume":"4","author":"Reunert","year":"2015","journal-title":"EBioMedicine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.cca.2014.07.010","article-title":"A New Simple and Rapid LC-ESI-MS\/MS Method for Quantification of Plasma Oxysterols as Dimethylaminobutyrate Esters. Its Successful Use for the Diagnosis of Niemann-Pick Type C Disease","volume":"437","author":"Boenzi","year":"2014","journal-title":"Clin. Chim. Acta"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/s13023-015-0274-1","article-title":"A Novel, Highly Sensitive and Specific Biomarker for Niemann-Pick Type C1 Disease","volume":"10","author":"Giese","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Welford, R.W.D., Garzotti, M., Louren\u00e7o, C.M., Mengel, E., Marquardt, T., Reunert, J., Amraoui, Y., Kolb, S.A., Morand, O., and Groenen, P. (2014). Plasma Lysosphingomyelin Demonstrates Great Potential as a Diagnostic Biomarker for Niemann-Pick Disease Type C in a Retrospective Study. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0114669"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"337ra63","DOI":"10.1126\/scitranslmed.aaf2326","article-title":"Development of a Bile Acid-Based Newborn Screen for Niemann-Pick Disease Type C","volume":"8","author":"Jiang","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"S78","DOI":"10.1016\/j.ymgme.2015.12.354","article-title":"Identification of New Biomarkers Suitable for an Early Diagnosis of Niemann-Pick C1","volume":"117","author":"Mazzacuva","year":"2016","journal-title":"Mol. Genet. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1212\/CPJ.0000000000000399","article-title":"Recommendations for the Detection and Diagnosis of Niemann-Pick Disease Type C: An Update","volume":"7","author":"Patterson","year":"2017","journal-title":"Neurol. Clin. Pract."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Maekawa, M., Jinnoh, I., Matsumoto, Y., Narita, A., Mashima, R., Takahashi, H., Iwahori, A., Saigusa, D., Fujii, K., and Abe, A. (2019). Structural Determination of Lysosphingomyelin-509 and Discovery of Novel Class Lipids from Patients with Niemann-Pick Disease Type C. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20205018"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1194\/jlr.RA119000157","article-title":"N-Acyl-O-Phosphocholineserines: Structures of a Novel Class of Lipids That Are Biomarkers for Niemann-Pick C1 Disease","volume":"60","author":"Sidhu","year":"2019","journal-title":"J. Lipid Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.ymgme.2012.03.012","article-title":"Recommendations for the Diagnosis and Management of Niemann-Pick Disease Type C: An Update","volume":"106","author":"Patterson","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13023-018-0785-7","article-title":"Consensus Clinical Management Guidelines for Niemann-Pick Disease Type C","volume":"13","author":"Geberhiwot","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5292","DOI":"10.1038\/s41598-019-41707-y","article-title":"Different Niemann-Pick C1 Genotypes Generate Protein Phenotypes That Vary in Their Intracellular Processing, Trafficking and Localization","volume":"9","author":"Shammas","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/1750-1172-5-16","article-title":"Niemann-Pick Disease Type C","volume":"5","author":"Vanier","year":"2010","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1086\/320606","article-title":"Niemann-Pick C1 Disease: Correlations between NPC1 Mutations, Levels of NPC1 Protein, and Phenotypes Emphasize the Functional Significance of the Putative Sterol-Sensing Domain and of the Cysteine-Rich Luminal Loop","volume":"68","author":"Millat","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1007\/s004390100531","article-title":"Niemann-Pick Type C Disease: NPC1 Mutations Associated with Severe and Mild Cellular Cholesterol Trafficking Alterations","volume":"109","author":"Ribeiro","year":"2001","journal-title":"Hum. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1038\/s41431-023-01408-7","article-title":"At a Glance: The Largest Niemann-Pick Type C1 Cohort with 602 Patients Diagnosed over 15 Years","volume":"31","author":"Pardo","year":"2023","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1002\/humu.10255","article-title":"Identification of 58 Novel Mutations in Niemann-Pick Disease Type C: Correlation with Biochemical Phenotype and Importance of PTC1-like Domains in NPC1","volume":"22","author":"Park","year":"2003","journal-title":"Hum. Mutat."},{"key":"ref_29","unstructured":"Gieselmann, V. (2006). Fabry Disease: Perspectives from 5 Years of FOS, Oxford PharmaGenesis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1056\/NEJM199101033240104","article-title":"Molecular Basis of Different Forms of Metachromatic Leukodystrophy","volume":"324","author":"Polten","year":"1991","journal-title":"N. Engl. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1172\/JCI115863","article-title":"An Unusual Splicing Mutation in the HEXB Gene Is Associated with Dramatically Different Phenotypes in Patients from Different Racial Backgrounds","volume":"90","author":"McInnes","year":"1992","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.jbiotec.2020.03.012","article-title":"Pre-MRNA Splicing Defects and RNA Binding Protein Involvement in Niemann Pick Type C Disease","volume":"318","author":"Paron","year":"2020","journal-title":"J. Biotechnol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1086\/324068","article-title":"Niemann-Pick Disease Type C: Spectrum of HE1 Mutations and Genotype\/Phenotype Correlations in the NPC2 Group","volume":"69","author":"Millat","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1908","DOI":"10.1194\/jlr.M200203-JLR200","article-title":"Niemann-Pick Type C Disease: Mutations of NPC1 Gene and Evidence of Abnormal Expression of Some Mutant Alleles in Fibroblasts","volume":"43","author":"Tarugi","year":"2002","journal-title":"J. Lipid Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.ymgme.2009.01.007","article-title":"Nonsense-Mediated MRNA Decay Process in Nine Alleles of Niemann-Pick Type C Patients from Spain","volume":"97","author":"Gort","year":"2009","journal-title":"Mol. Genet. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1007\/s004399900059","article-title":"NPC1 Gene Mutations in Japanese Patients with Niemann-Pick Disease Type C","volume":"105","author":"Yamamoto","year":"1999","journal-title":"Hum. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e1451","DOI":"10.1002\/mgg3.1451","article-title":"NPC1 Silent Variant Induces Skipping of Exon 11 (p.V562V) and Unfolded Protein Response Was Found in a Specific Niemann-Pick Type C Patient","volume":"8","author":"Coutinho","year":"2020","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1111\/j.1399-0004.2005.00490.x","article-title":"Identification of 25 New Mutations in 40 Unrelated Spanish Niemann-Pick Type C Patients: Genotype-Phenotype Correlations","volume":"68","author":"Ballart","year":"2005","journal-title":"Clin. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1101\/gad.1195304","article-title":"Computational Definition of Sequence Motifs Governing Constitutive Exon Splicing","volume":"18","author":"Zhang","year":"2004","journal-title":"Genes Dev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/j.molcel.2006.05.008","article-title":"Comparative Analysis Identifies Exonic Splicing Regulatory Sequences-The Complex Definition of Enhancers and Silencers","volume":"22","author":"Goren","year":"2006","journal-title":"Mol. Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1186\/s13023-018-0913-4","article-title":"Adult Niemann-Pick Disease Type C in France: Clinical Phenotypes and Long-Term Miglustat Treatment Effect","volume":"13","author":"Nadjar","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1007\/s00415-013-7159-9","article-title":"Heterogeneity and Frequency of Movement Disorders in Juvenile and Adult-Onset Niemann-Pick C Disease","volume":"261","author":"Anheim","year":"2014","journal-title":"J. Neurol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"18563","DOI":"10.1016\/S0021-9258(19)81396-0","article-title":"Multiple Abnormal Beta-Hexosaminidase Alpha Chain MRNAs in a Compound-Heterozygous Ashkenazi Jewish Patient with Tay-Sachs Disease","volume":"263","author":"Ohno","year":"1988","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1186\/s13023-019-1124-3","article-title":"Evaluation of Different Suspicion Indices in Identifying Patients with Niemann-Pick Disease Type C in Clinical Practice: A Post Hoc Analysis of a Retrospective Chart Review","volume":"14","author":"Pineda","year":"2019","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_45","first-page":"5265686","article-title":"Comparison of In Silico Tools for Splice-Altering Variant Prediction Using Established Spliceogenic Variants: An End-User\u2019s Point of View","volume":"2022","author":"Jang","year":"2022","journal-title":"Int. J. Genom."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/j.ajhg.2023.06.002","article-title":"Using the ACMG\/AMP Framework to Capture Evidence Related to Predicted and Observed Impact on Splicing: Recommendations from the ClinGen SVI Splicing Subgroup","volume":"110","author":"Walker","year":"2023","journal-title":"Am. J. Hum. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"8212","DOI":"10.1073\/pnas.1607795113","article-title":"Structure of Human Niemann-Pick C1 Protein","volume":"113","author":"Li","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1016\/j.cell.2016.05.022","article-title":"Structural Insights into the Niemann-Pick C1 (NPC1)-Mediated Cholesterol Transfer and Ebola Infection","volume":"165","author":"Gong","year":"2016","journal-title":"Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"282","DOI":"10.12688\/f1000research.5654.1","article-title":"Interpretation of MRNA Splicing Mutations in Genetic Disease: Review of the Literature and Guidelines for Information-Theoretical Analysis","volume":"3","author":"Caminsky","year":"2014","journal-title":"F1000Research"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/s13353-018-0444-7","article-title":"Splicing Mutations in Human Genetic Disorders: Examples, Detection, and Confirmation","volume":"59","author":"Anna","year":"2018","journal-title":"J. Appl. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"108444","DOI":"10.1016\/j.mrrev.2022.108444","article-title":"Code inside the Codon: The Role of Synonymous Mutations in Regulating Splicing Machinery and Its Impact on Disease","volume":"790","author":"Sarkar","year":"2022","journal-title":"Mutat. Res. Rev. Mutat. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1111\/j.1399-0004.2010.01504.x","article-title":"Molecular Analysis of 30 Niemann-Pick Type C Patients from Spain","volume":"80","author":"Lluch","year":"2011","journal-title":"Clin. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1002\/humu.23063","article-title":"Mini-Exome Coupled to Read-Depth Based Copy Number Variation Analysis in Patients with Inherited Ataxias","volume":"37","author":"Marelli","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Dardis, A., Zampieri, S., Gellera, C., Carrozzo, R., Cattarossi, S., Peruzzo, P., Dariol, R., Sechi, A., Deodato, F., and Caccia, C. (2020). Molecular Genetics of Niemann\u2013Pick Type C Disease in Italy: An Update on 105 Patients and Description of 18 NPC1 Novel Variants. J. Clin. Med., 9.","DOI":"10.3390\/jcm9030679"},{"key":"ref_55","first-page":"308","article-title":"Molecular and Functional Study of Pediatric Patients with Niemann-Pick C in Argentina","volume":"82","author":"Terada","year":"2022","journal-title":"Medicina"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s10048-009-0175-3","article-title":"Molecular Analysis of NPC1 and NPC2 Gene in 34 Niemann-Pick C Italian Patients: Identification and Structural Modeling of Novel Mutations","volume":"10","author":"Fancello","year":"2009","journal-title":"Neurogenetics"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Imrie, J., Heptinstall, L., Knight, S., and Strong, K. (2015). Observational Cohort Study of the Natural History of Niemann-Pick Disease Type C in the UK: A 5-Year Update from the UK Clinical Database. BMC Neurol., 15.","DOI":"10.1186\/s12883-015-0511-1"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1002\/humu.9287","article-title":"A Point Mutation in the Lariat Branch Point of Intron 6 of NPC1 as the Cause of Abnormal Pre-MRNA Splicing in Niemann-Pick Type C Disease","volume":"24","author":"Panico","year":"2004","journal-title":"Hum. Mutat."},{"key":"ref_59","first-page":"419","article-title":"Blood 7-ketocholesterol level, clinical features and gene mutation analysis of 18 children with Niemann-Pick disease type C","volume":"54","author":"Zhan","year":"2016","journal-title":"Zhonghua Er Ke Za Zhi Chin. J. Pediatr."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1194\/jlr.P013524","article-title":"Niemann-Pick Type C Disease: Characterizing Lipid Levels in Patients with Variant Lysosomal Cholesterol Storage","volume":"52","author":"Weber","year":"2011","journal-title":"J. Lipid Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"E993","DOI":"10.1002\/humu.21119","article-title":"Antisense Oligonucleotide Treatment for a Pseudoexon-Generating Mutation in the NPC1 Gene Causing Niemann-Pick Type C Disease","volume":"30","author":"Coll","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1086\/320599","article-title":"Niemann-Pick C Variant Detection by Altered Sphingolipid Trafficking and Correlation with Mutations within a Specific Domain of NPC1","volume":"68","author":"Sun","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1515\/jpem-2021-0052","article-title":"Niemann-Pick Type C Disease with a Novel Intronic Mutation: Three Turkish Cases from the Same Family","volume":"35","author":"Yarar","year":"2022","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1038\/s41431-022-01119-5","article-title":"An Integrated Multiomic Approach as an Excellent Tool for the Diagnosis of Metabolic Diseases: Our First 3720 Patients","volume":"30","author":"Almeida","year":"2022","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_65","first-page":"284","article-title":"Clinical features and gene mutation analysis of patients with Niemann-Pick disease type C","volume":"98","author":"Ren","year":"2018","journal-title":"Zhonghua Yi Xue Za Zhi"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1002\/ajmg.a.38104","article-title":"Association of NPC1 Variant p.P237S with a Pathogenic Splice Variant in Two Niemann-Pick Disease Type C1 Patients","volume":"173","author":"Salman","year":"2017","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1186\/s13023-016-0510-3","article-title":"Thirteen Year Retrospective Review of the Spectrum of Inborn Errors of Metabolism Presenting in a Tertiary Center in Saudi Arabia","volume":"11","author":"Alfadhel","year":"2016","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/1750-1172-7-36","article-title":"Miglustat Therapy in the French Cohort of Paediatric Patients with Niemann-Pick Disease Type C","volume":"7","author":"Valayannopoulos","year":"2012","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s13073-021-00855-5","article-title":"Integration of Whole Genome Sequencing into a Healthcare Setting: High Diagnostic Rates across Multiple Clinical Entities in 3219 Rare Disease Patients","volume":"13","author":"Stranneheim","year":"2021","journal-title":"Genome Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1007\/s00415-019-09358-1","article-title":"Multi-Gene Testing in Neurological Disorders Showed an Improved Diagnostic Yield: Data from over 1000 Indian Patients","volume":"266","author":"Ganapathy","year":"2019","journal-title":"J. Neurol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1111\/cge.14037","article-title":"Clinical and Genetic Spectrum of 104 Indian Families with Central Nervous System White Matter Abnormalities","volume":"100","author":"Kaur","year":"2021","journal-title":"Clin. Genet."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/8904_2011_49","article-title":"Treatment of Human Fibroblasts Carrying NPC1 Missense Mutations with MG132 Leads to an Improvement of Intracellular Cholesterol Trafficking","volume":"2","author":"Zampieri","year":"2012","journal-title":"JIMD Rep."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"102704","DOI":"10.1016\/j.bcmd.2022.102704","article-title":"Influence of Initial Clinical Suspicion on the Diagnostic Yield of Laboratory Enzymatic Testing in Lysosomal Storage Disorders. Experience from a Multispecialty Hospital","volume":"98","year":"2023","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3167","DOI":"10.1007\/s00415-021-10918-7","article-title":"Genetic and Phenotypic Variability in Adult Patients with Niemann Pick Type C from Serbia: Single-Center Experience","volume":"269","year":"2022","journal-title":"J. Neurol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1186\/1750-1172-9-82","article-title":"Diagnosis of Niemann-Pick Disease Type C with 7-Ketocholesterol Screening Followed by NPC1\/NPC2 Gene Mutation Confirmation in Chinese Patients","volume":"9","author":"Zhang","year":"2014","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.jns.2013.08.033","article-title":"Parkinsonism Syndrome in Heterozygotes for Niemann-Pick C1","volume":"335","author":"Kluenemann","year":"2013","journal-title":"J. Neurol. Sci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2557","DOI":"10.1007\/s00415-015-7889-y","article-title":"NPC1 Is Enriched in Unexplained Early Onset Ataxia: A Targeted High-Throughput Screening","volume":"262","author":"Synofzik","year":"2015","journal-title":"J. Neurol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1038\/s41436-018-0293-0","article-title":"Putting Genome-Wide Sequencing in Neonates into Perspective","volume":"21","author":"Aten","year":"2019","journal-title":"Genet. Med."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/11\/1990\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:11:24Z","timestamp":1760130684000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/11\/1990"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,25]]},"references-count":78,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["genes14111990"],"URL":"https:\/\/doi.org\/10.3390\/genes14111990","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,25]]}}}