{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T12:34:26Z","timestamp":1791462866066,"version":"4.3.4"},"reference-count":22,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,16]],"date-time":"2021-04-16T00:00:00Z","timestamp":1618531200000},"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:p><jats:bold>Background:<\/jats:bold> Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are two subtypes of muscular dystrophy diseases caused by pathogenic mutations in the <jats:italic>DMD<\/jats:italic> gene. Until now, more than 4,600 disease-causing mutations in <jats:italic>DMD<\/jats:italic> have been reported. However, only 33 mutations were deep intronic, cases with this type of mutations were limited.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> In this study, we used a combination of complementary DNA (cDNA) and target DNA sequencing analysis in addition to conventional whole-exome sequencing (WES).<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Three novel hemizygous mutations IVS11 + 17811C &amp;gt; G (c.1331 + 17811C &amp;gt; G), IVS21 + 3252A &amp;gt; G (c.2803 + 3252A &amp;gt; G) and IVS40 + 362A &amp;gt; G (c.5739 + 362A &amp;gt; G) were identified in DMD patients, while a reported hemizygous mutation IVS62-285A &amp;gt; G (c.9225-285A &amp;gt; G) was found in the BMD patient. These <jats:italic>DMD<\/jats:italic> mutations lead to pseudoexon insertions, causing the generation of truncated and dysfunctional dystrophin.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> This study defines three novel and one reported intronic mutations, which can result in DMD\/BMD. We also emphasize the need to combine WES and cDNA-based methods to detect the variant in the very large <jats:italic>DMD<\/jats:italic> gene in which the mutational spectrum is complex.<\/jats:p>","DOI":"10.3389\/fgene.2021.657040","type":"journal-article","created":{"date-parts":[[2021,4,16]],"date-time":"2021-04-16T19:01:22Z","timestamp":1618599682000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Novel Intronic Mutations Introduce Pseudoexons in DMD That Cause Muscular Dystrophy in Patients"],"prefix":"10.3389","volume":"12","author":[{"given":"Xinguo","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxi","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Mai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianping","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianxiang","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanqi","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,16]]},"reference":[{"key":"B1","first-page":"54","article-title":"Exploring the molecular basis for variability among patients with Becker muscular dystrophy: dystrophin gene and protein studies.","volume":"49","author":"Beggs","year":"1991","journal-title":"Am. J. Hum. Genet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/s0960-8966(03)00169-x","article-title":"Dystrophinopathy caused by mid-intronic substitutions activating cryptic exons in the DMD gene.","volume":"14","author":"Beroud","year":"2004","journal-title":"Neuromuscul. Disord."},{"key":"B3","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1007\/bf00858726","article-title":"The clinical, genetic and dystrophin characteristics of Becker muscular dystrophy. II. Correlation of phenotype with genetic and protein abnormalities.","volume":"240","author":"Bushby","year":"1993","journal-title":"J. Neurol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1016\/j.gene.2012.09.037","article-title":"A new deletion in 5\u2019-end of dystrophin gene removing M and P promoters and dystrophin muscle enhancers.","volume":"511","author":"Cau","year":"2012","journal-title":"Gene"},{"key":"B5","doi-asserted-by":"publisher","first-page":"5","DOI":"10.3233\/prm-160361","article-title":"Age at onset of first signs or symptoms predicts age at loss of ambulation in Duchenne and Becker muscular dystrophy: data from the MD STARnet.","volume":"9","author":"Ciafaloni","year":"2016","journal-title":"J. Pediatr. Rehabil. Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1002\/ajmg.a.30617","article-title":"Improved molecular diagnosis of dystrophinopathies in an unselected clinical cohort.","volume":"134","author":"Dent","year":"2005","journal-title":"Am. J. Med. Genet. Part A"},{"key":"B7","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1212\/wnl.0000000000002337","article-title":"Practice guideline update summary: corticosteroid treatment of Duchenne muscular dystrophy: report of the guideline development subcommittee of the American academy of neurology.","volume":"86","author":"Gloss","year":"2016","journal-title":"Neurology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1016\/j.ajhg.2019.01.012","article-title":"Expanding the boundaries of RNA sequencing as a diagnostic tool for rare Mendelian disease.","volume":"104","author":"Gonorazky","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"B9","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1002\/ana.21290","article-title":"DMD pseudoexon mutations: splicing efficiency, phenotype, and potential therapy.","volume":"63","author":"Gurvich","year":"2008","journal-title":"Ann. Neurol."},{"key":"B10","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1002\/(SICI)1098-1004(1999)13:2<170::AID-HUMU12>3.0.CO;2-7","article-title":"Newly recognized exons induced by a splicing abnormality from an intronic mutation of the dystrophin gene resulting in Duchenne muscular dystrophy. Mutations in brief no. 213. Online.","volume":"13","author":"Ikezawa","year":"1999","journal-title":"Hum. Mutat."},{"key":"B11","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","article-title":"Predicting splicing from primary sequence with deep learning.","volume":"176","author":"Jaganathan","year":"2019","journal-title":"Cell"},{"key":"B12","doi-asserted-by":"publisher","first-page":"77","DOI":"10.3233\/jnd-190431","article-title":"Pseudoexons of the DMD Gene.","volume":"7","author":"Keegan","year":"2020","journal-title":"J. Neuromuscul. Dis."},{"key":"B13","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1002\/humu.21471","article-title":"Pure intronic rearrangements leading to aberrant pseudoexon inclusion in dystrophinopathy: a new class of mutations?","volume":"32","author":"Khelifi","year":"2011","journal-title":"Hum. Mutat."},{"key":"B14","doi-asserted-by":"publisher","first-page":"D980","DOI":"10.1093\/nar\/gkt1113","article-title":"ClinVar: public archive of relationships among sequence variation and human phenotype.","volume":"42","author":"Landrum","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1610","DOI":"10.1007\/s00415-011-5979-z","article-title":"Genotype and phenotype characterization in a large dystrophinopathic cohort with extended follow-up.","volume":"258","author":"Magri","year":"2011","journal-title":"J. Neurol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1038\/jhg.2016.7","article-title":"Genetic diagnosis of Duchenne\/Becker muscular dystrophy using next-generation sequencing: validation analysis of DMD mutations.","volume":"61","author":"Okubo","year":"2016","journal-title":"J. Hum. Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.tig.2012.01.001","article-title":"New connections between splicing and human disease.","volume":"28","author":"Padgett","year":"2012","journal-title":"Trends Genet."},{"key":"B18","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1007\/s12098-017-2455-5","article-title":"Next generation sequencing in diagnosis of MLPA Negative cases presenting as Duchenne\/Becker muscular dystrophies.","volume":"85","author":"Singh","year":"2018","journal-title":"Indian J. Pediatr."},{"key":"B19","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1007\/s00439-017-1779-6","article-title":"The human gene mutation database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies.","volume":"136","author":"Stenson","year":"2017","journal-title":"Hum. Genet."},{"key":"B20","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1002\/humu.10214","article-title":"Pseudoexon activation in the DMD gene as a novel mechanism for Becker muscular dystrophy.","volume":"21","author":"Tuffery-Giraud","year":"2003","journal-title":"Hum. Mutat."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1007\/s00439-017-1809-4","article-title":"Deep intronic mutations and human disease.","volume":"136","author":"Vaz-Drago","year":"2017","journal-title":"Hum. Genet."},{"key":"B22","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/j.nmd.2017.04.003","article-title":"Deep intronic variants introduce DMD pseudoexon in patient with muscular dystrophy.","volume":"27","author":"Zaum","year":"2017","journal-title":"Neuromuscul. Disord."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2021.657040\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,16]],"date-time":"2021-04-16T19:01:25Z","timestamp":1618599685000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2021.657040\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,16]]},"references-count":22,"alternative-id":["10.3389\/fgene.2021.657040"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2021.657040","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,16]]},"article-number":"657040"}}