{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:54:35Z","timestamp":1753890875296,"version":"3.41.2"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder characterized by caf\u00e9-au-lait macules, neurofibromas, and other manifestations. It is caused by variations in the <jats:italic>NF1<\/jats:italic> gene located on chromosome 17q11.2. The gene\u2019s complexity and extensive variations often lead to misdiagnoses by conventional detection methods, which adverses to effective diagnosis and treatment strategies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Case presentation<\/jats:title><jats:p>A 26-year-old Chinese woman was admitted to our hospital with multiple caf\u00e9-au-lait spots and cutaneous nodules. She had a family history of NF1, with her mother also showing similar dermatological symptoms. Whole exome sequencing (WES) identified a synonymous variation, NM_001042492.3: c.987A&amp;gt;G (p.K329K), in the <jats:italic>NF1<\/jats:italic> gene. Although synonymous variations are typically considered non-pathogenic, RNA sequencing (RNA-seq) and minigene analysis revealed that this variation caused the partial loss of exon 9, leading to aberrant splicing. These findings were validated through Sanger sequencing, confirming the genetic alteration and its impact on mRNA splicing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The case highlights the critical role of synonymous variations in the <jats:italic>NF1<\/jats:italic> gene that significantly impact splicing and protein function. These findings expand our understanding of <jats:italic>NF1<\/jats:italic>\u2019s genetic diversity and underscore the importance of comprehensive genetic and RNA analyses to achieve accurate diagnosis and in-depth insight into the molecular underpinnings of NF1.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fgene.2025.1572487","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T05:34:47Z","timestamp":1746768887000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A novel synonymous variant in the NF1 gene disrupting splicing contributes to neurofibromatosis pathogenesis"],"prefix":"10.3389","volume":"16","author":[{"given":"Tao","family":"Lin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zheyan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Biwen","family":"Dong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haojie","family":"Pan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hai","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xianjue","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaixin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanan","family":"Lai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenhui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ye","family":"Dong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zitong","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Menmen","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiujie","family":"Xi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuqi","family":"Xia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yimin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenhan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoqing","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Congcong","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanjun","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianqiong","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fan","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongping","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiayong","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/b978-0-444-62702-5.00004-4","article-title":"Neurofibromatosis type 1","volume":"132","author":"Anderson","year":"2015","journal-title":"Handb. Clin. Neurol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"e82","DOI":"10.1136\/jmg.40.6.e82","article-title":"Recurrent mutations in the NF1 gene are common among neurofibromatosis type 1 patients","volume":"40","author":"Ars","year":"2003","journal-title":"J. Med. Genet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1016\/0092-8674(90)90151-4","article-title":"The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins","volume":"63","author":"Ballester","year":"1990","journal-title":"Cell"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2365","DOI":"10.3390\/cells9112365","article-title":"Neurofibromin structure, functions and regulation","volume":"9","author":"Bergoug","year":"2020","journal-title":"Cells"},{"key":"B5","doi-asserted-by":"publisher","first-page":"20150474","DOI":"10.1098\/rstb.2015.0474","article-title":"Alternative splicing and the evolution of phenotypic novelty","volume":"372","author":"Bush","year":"2017","journal-title":"Philos. Trans. R. Soc. Lond B Biol. Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/nrg775","article-title":"Listening to silence and understanding nonsense: exonic mutations that affect splicing","volume":"3","author":"Cartegni","year":"2002","journal-title":"Nat. Rev. Genet."},{"key":"B7","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1038\/nrg1770","article-title":"Hearing silence: non-neutral evolution at synonymous sites in mammals","volume":"7","author":"Chamary","year":"2006","journal-title":"Nat. Rev. Genet."},{"key":"B8","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1159\/000134370","article-title":"Identification and mapping of type 1 neurofibromatosis (NF1) homologous loci","volume":"73","author":"Cummings","year":"1996","journal-title":"Cytogenet Cell Genet."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1767","DOI":"10.1039\/c004796c","article-title":"Silent mutations in sight: co-variations in tRNA abundance as a key to unravel consequences of silent mutations","volume":"6","author":"Czech","year":"2010","journal-title":"Mol. Biosyst."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2130","DOI":"10.1002\/humu.24487","article-title":"High-yield identification of pathogenic NF1 variants by skin fibroblast transcriptome screening after apparently normal diagnostic DNA testing","volume":"43","author":"Douben","year":"2022","journal-title":"Hum. Mutat."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1038\/ejhg.2011.113","article-title":"Mortality in neurofibromatosis 1: in North West England: an assessment of actuarial survival in a region of the UK since 1989","volume":"19","author":"Evans","year":"2011","journal-title":"Eur. J. Hum. Genet."},{"key":"B12","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1093\/bib\/bbk005","article-title":"Bioinformatics of alternative splicing and its regulation","volume":"7","author":"Florea","year":"2006","journal-title":"Brief. Bioinform"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.3390\/genes12091308","article-title":"Performance evaluation of SpliceAI for the prediction of splicing of NF1 variants","volume":"12","author":"Ha","year":"2021","journal-title":"Genes (Basel)"},{"key":"B14","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.celrep.2018.03.052","article-title":"Systematic analysis of splice-site-creating mutations in cancer","volume":"23","author":"Jayasinghe","year":"2018","journal-title":"Cell Rep."},{"key":"B15","doi-asserted-by":"publisher","first-page":"772958","DOI":"10.3389\/fgene.2021.772958","article-title":"Case report: a synonymous mutation in NF1 located at the non-canonical splicing site leading to exon 45 skipping","volume":"12","author":"Jin","year":"2021","journal-title":"Front. Genet."},{"key":"B16","doi-asserted-by":"publisher","first-page":"2145","DOI":"10.1093\/nar\/gky056","article-title":"The mechanisms of a mammalian splicing enhancer","volume":"46","author":"Jobbins","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1038\/s10038-019-0695-0","article-title":"Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types","volume":"65","author":"Kang","year":"2020","journal-title":"J. Hum. Genet."},{"key":"B18","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1136\/jmg.2008.059329","article-title":"Mosaicism in sporadic neurofibromatosis type 1: variations on a theme common to other hereditary cancer syndromes?","volume":"45","author":"Kehrer-Sawatzki","year":"2008","journal-title":"J. Med. Genet."},{"key":"B19","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1093\/nar\/gkl924","article-title":"Different levels of alternative splicing among eukaryotes","volume":"35","author":"Kim","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1177\/0022034520901708","article-title":"Alteration of exon definition causes amelogenesis imperfecta","volume":"99","author":"Kim","year":"2020","journal-title":"J. Dent. Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"104182","DOI":"10.1016\/j.ejmg.2021.104182","article-title":"A synonymous variant in a non-canonical exon of CDC45 disrupts splicing in two affected sibs with Meier-Gorlin syndrome with craniosynostosis","volume":"64","author":"Knapp","year":"2021","journal-title":"Eur. J. Med. Genet."},{"key":"B22","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1038\/s41525-021-00258-w","article-title":"Pathogenic neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq","volume":"6","author":"Koster","year":"2021","journal-title":"NPJ Genom Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/s12881-020-0976-7","article-title":"Case report: a synonymous VHL mutation (c.414A > G, p.Pro138Pro) causes pathogenic familial hemangioblastoma through dysregulated splicing","volume":"21","author":"Liu","year":"2020","journal-title":"BMC Med. Genet."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1089053","DOI":"10.3389\/fgene.2023.1089053","article-title":"Re-evaluating the impact of alternative RNA splicing on proteomic diversity","volume":"14","author":"Manuel","year":"2023","journal-title":"Front. Genet."},{"key":"B25","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1002\/1098-1004(200006)15:6<541::Aid-humu6>3.0.Co;2-n","article-title":"Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects","volume":"15","author":"Messiaen","year":"2000","journal-title":"Hum. Mutat."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e25","DOI":"10.1136\/jmg.2004.029629","article-title":"Pitfalls of automated comparative sequence analysis as a single platform for routine clinical testing for NF1","volume":"42","author":"Messiaen","year":"2005","journal-title":"J. Med. Genet."},{"key":"B28","doi-asserted-by":"publisher","first-page":"R19","DOI":"10.1186\/gb-2014-15-1-r19","article-title":"MutPred Splice: machine learning-based prediction of exonic variants that disrupt splicing","volume":"15","author":"Mort","year":"2014","journal-title":"Genome Biol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"102173","DOI":"10.1016\/j.isci.2021.102173","article-title":"A BAP1 synonymous mutation results in exon skipping, loss of function and worse patient prognosis","volume":"24","author":"Niersch","year":"2021","journal-title":"iScience"},{"key":"B30","doi-asserted-by":"publisher","first-page":"6368","DOI":"10.1073\/pnas.0502288102","article-title":"Synonymous mutations in CFTR exon 12 affect splicing and are not neutral in evolution","volume":"102","author":"Pagani","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1175","DOI":"10.1007\/s00438-017-1350-0","article-title":"The determinants of alternative RNA splicing in human cells","volume":"292","author":"Ramanouskaya","year":"2017","journal-title":"Mol. Genet. Genomics"},{"key":"B27","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med"},{"key":"B32","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.gene.2016.04.057","article-title":"Towards understanding pre-mRNA splicing mechanisms and the role of SR proteins","volume":"587","author":"Sahebi","year":"2016","journal-title":"Gene"},{"key":"B33","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1038\/nrg3051","article-title":"Understanding the contribution of synonymous mutations to human disease","volume":"12","author":"Sauna","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.3390\/cancers13081879","article-title":"Genotype-phenotype correlations in neurofibromatosis type 1: a single-center cohort study","volume":"13","author":"Scala","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B35","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1038\/d41586-022-01091-6","article-title":"Mutations matter even if proteins stay the same","volume":"606","author":"Sharp","year":"2022","journal-title":"Nature"},{"key":"B36","doi-asserted-by":"publisher","first-page":"e23685","DOI":"10.1016\/j.heliyon.2023.e23685","article-title":"Neurofibromatosis type 1: clinical characteristics and mutation spectrum in a North Indian cohort","volume":"10","author":"Srivastava","year":"2024","journal-title":"Heliyon"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1399-0004.2006.00639.x","article-title":"Neurofibromin: a general outlook","volume":"70","author":"Trov\u00f3-Marqui","year":"2006","journal-title":"Clin. Genet."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1811","DOI":"10.1002\/humu.24091","article-title":"Large\u2010scale comparative evaluation of user\u2010friendly tools for predicting variant\u2010induced alterations of splicing regulatory elements","volume":"41","author":"Tubeuf","year":"2020","journal-title":"Hum. Mutat."},{"key":"B39","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1038\/jid.2014.465","article-title":"Incidence and mortality of neurofibromatosis: a total population study in Finland","volume":"135","author":"Uusitalo","year":"2015","journal-title":"J. Invest Dermatol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.tree.2021.11.010","article-title":"The role of alternative splicing in adaptation and evolution","volume":"37","author":"Verta","year":"2022","journal-title":"Trends Ecol. Evol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1038\/nrg2164","article-title":"Splicing in disease: disruption of the splicing code and the decoding machinery","volume":"8","author":"Wang","year":"2007","journal-title":"Nat. Rev. Genet."},{"key":"B42","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1002\/path.2649","article-title":"The pathobiology of splicing","volume":"220","author":"Ward","year":"2010","journal-title":"J. Pathol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"2345","DOI":"10.2147\/ccid.S388045","article-title":"NF1 gene novel splicing mutations in a Chinese family with neurofibromatosis type 1: case series","volume":"15","author":"Wu","year":"2022","journal-title":"Clin. Cosmet. Investig. Dermatol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"991314","DOI":"10.3389\/fgene.2022.991314","article-title":"Clinical characteristics and in silico analysis of congenital pseudarthrosis of the tibia combined with neurofibromatosis type 1 caused by a novel NF1 mutation","volume":"13","author":"Xu","year":"2022","journal-title":"Front. Genet."},{"key":"B45","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.gene.2006.05.015","article-title":"Alternative splicing in human transcriptome: functional and structural influence on proteins","volume":"380","author":"Yura","year":"2006","journal-title":"Gene"},{"key":"B46","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/978-3-031-05616-1_6","article-title":"An examination of mechanisms by which synonymous mutations may alter protein levels, structure and functions","volume-title":"Single nucleotide polymorphisms: human variation and a coming revolution in biology and medicine","author":"Zhang","year":"2022"},{"key":"B47","doi-asserted-by":"publisher","first-page":"592611","DOI":"10.3389\/fgene.2020.592611","article-title":"A comprehensive analysis and splicing characterization of naturally occurring synonymous variants in the ATP7B gene","volume":"11","author":"Zhou","year":"2020","journal-title":"Front. Genet."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1572487\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T05:34:49Z","timestamp":1746768889000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1572487\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,9]]},"references-count":47,"alternative-id":["10.3389\/fgene.2025.1572487"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2025.1572487","relation":{},"ISSN":["1664-8021"],"issn-type":[{"type":"electronic","value":"1664-8021"}],"subject":[],"published":{"date-parts":[[2025,5,9]]},"article-number":"1572487"}}