{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T12:02:12Z","timestamp":1781265732092,"version":"3.54.1"},"reference-count":49,"publisher":"BMJ","issue":"3","funder":[{"name":"Association Fran\u00e7aise contre les Myopathies","award":["21576"],"award-info":[{"award-number":["21576"]}]},{"name":"Vicerrector\u00eda de Investigaci\u00f3n of the Universidad de Costa Rica","award":["742\u00adB8\u00ad506"],"award-info":[{"award-number":["742\u00adB8\u00ad506"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2025,10,13]]},"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Myotonic dystrophy type 1 (DM1) is a multisystem disorder with autosomal dominant inheritance, caused by the abnormal expansion of the CTG triplet in the\n                      <jats:italic>DMPK<\/jats:italic>\n                      gene. Biomarker discovery in DM1 is crucial for monitoring disease progression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed RNA sequencing on blood, skin and muscle samples from the same patients to assess splicing events. Mis-splicing events were identified using the Mann-Whitney U rank-sum test, and per cent spliced in for exons was correlated with repeat expansion size using Spearman\u2019s correlation. We also examined the relationship between mis-splicing and disease severity through Fisher\u2019s exact test and correlation analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified 937, 384 and 1216 mis-splicing events in muscle, blood and skin, respectively. Of these, 52 exons in muscle and 10 in blood correlated with estimated progenitor allele length (false discovery rate (FDR) &lt;0.1), but none in skin. Notably, nine exons in blood correlated with total muscle mis-splicing (FDR&lt;0.05), suggesting their potential as biomarkers of severity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This is the first study to identify splicing dysregulation in blood and skin in patients with DM1 and identify novel potential blood-based mis-splicing biomarkers for disease severity. The correlation between several blood exons and the muscle splicing dysregulation indicates that blood-based biomarkers can be valuable for assessing disease severity, monitoring disease progression and evaluating treatment efficacy. Larger sample sizes may be necessary to clarify the relationship between mis-splicing and disease severity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmg-2025-110919","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T07:17:43Z","timestamp":1761722263000},"page":"164-173","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Analysis of muscle and blood RNA samples from patients with myotonic dystrophy type 1 reveals the presence of new mis-splicing biomarkers of disease severity"],"prefix":"10.1136","volume":"63","author":[{"given":"Melissa","family":"Palma-Jim\u00e9nez","sequence":"first","affiliation":[{"name":"INISA, Universidad de Costa Rica, San Jos\u00e9, Costa Rica"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisbeth","family":"Ramirez-Carvajal","sequence":"additional","affiliation":[{"name":"INISA, Universidad de Costa Rica, San Jos\u00e9, Costa Rica"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eyleen","family":"Corrales","sequence":"additional","affiliation":[{"name":"INISA, Universidad de Costa Rica, San Jos\u00e9, Costa Rica"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailey","family":"Olafson","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, College of Medicine, University of Florida, Gainesville, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric T","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, College of Medicine, University of Florida, Gainesville, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6564-8671","authenticated-orcid":false,"given":"Fernando","family":"Morales","sequence":"additional","affiliation":[{"name":"INISA, Universidad de Costa Rica, San Jos\u00e9, Costa Rica"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,10,28]]},"reference":[{"key":"2026061204451530000_63.3.164.1","doi-asserted-by":"publisher","DOI":"10.1016\/0960-8966(91)90039-U"},{"key":"2026061204451530000_63.3.164.2","unstructured":"Harper PS . 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RNA-dominant diseases. Hum Mol Genet 2006;R162\u20139. doi:10.1093\/hmg\/ddl181","DOI":"10.1093\/hmg\/ddl181"},{"key":"2026061204451530000_63.3.164.14","doi-asserted-by":"publisher","DOI":"10.1042\/BST0371281"},{"key":"2026061204451530000_63.3.164.15","doi-asserted-by":"publisher","DOI":"10.1002\/ana.23992"},{"key":"2026061204451530000_63.3.164.16","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1006316","article-title":"Dose-Dependent Regulation of Alternative Splicing by MBNL Proteins Reveals Biomarkers for Myotonic Dystrophy","volume":"12","author":"Wagner","year":"2016","journal-title":"PLoS Genet"},{"key":"2026061204451530000_63.3.164.17","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy432"},{"key":"2026061204451530000_63.3.164.18","doi-asserted-by":"crossref","first-page":"2784","DOI":"10.1007\/s00415-021-10917-8","article-title":"Splicing in two skeletal muscle transcripts correlates with clinical phenotype in myotonic dystrophy type 1 patients","volume":"269","author":"Sedehizadeh","year":"2022","journal-title":"J Neurol"},{"key":"2026061204451530000_63.3.164.19","doi-asserted-by":"crossref","first-page":"2496","DOI":"10.1093\/hmg\/ddaa123","article-title":"Longitudinal increases in somatic mosaicism of the expanded CTG repeat in myotonic dystrophy type 1 are associated with variation in age-at-onset","volume":"29","author":"Morales","year":"2020","journal-title":"Hum Mol Genet"},{"key":"2026061204451530000_63.3.164.20","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.8b00300"},{"key":"2026061204451530000_63.3.164.21","doi-asserted-by":"publisher","DOI":"10.1602\/neurorx.1.2.182"},{"key":"2026061204451530000_63.3.164.22","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-018-06206-0","article-title":"Analysis of extracellular mRNA in human urine reveals splice variant biomarkers of muscular dystrophies","volume":"9","author":"Antoury","year":"2018","journal-title":"Nat Commun"},{"key":"2026061204451530000_63.3.164.23","doi-asserted-by":"crossref","first-page":"512","DOI":"10.4103\/neuroindia.NI_237_16","article-title":"Deregulation of microRNAs in blood and skeletal muscles of myotonic dystrophy type 1 patients","volume":"65","author":"Ambrose","year":"2017","journal-title":"Neurol India"},{"key":"2026061204451530000_63.3.164.24","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.omtm.2021.09.007","article-title":"miR-223-3p and miR-24-3p as novel serum-based biomarkers for myotonic dystrophy type 1","volume":"23","author":"Koutalianos","year":"2021","journal-title":"Mol Ther Methods Clin Dev"},{"key":"2026061204451530000_63.3.164.25","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1289\/ehp.9334","article-title":"Using biomarkers to inform cumulative risk assessment","volume":"115","author":"Ryan","year":"2007","journal-title":"Environ Health Perspect"},{"key":"2026061204451530000_63.3.164.26","doi-asserted-by":"publisher","DOI":"10.1586\/14737159.3.5.525"},{"key":"2026061204451530000_63.3.164.27","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddac231"},{"key":"2026061204451530000_63.3.164.28","unstructured":"Wang ET , Treacy D , Wang TT , et al . Data from: transcriptional profiling of myotonic dystrophy muscle and heart. Gene expression omnibus (GEO), series GSE86356. 2020. Available: https:\/\/doi.org\/10.25585\/14845058"},{"key":"2026061204451530000_63.3.164.29","unstructured":"Shin H , Shannon CP , Fishbane N , et al . Data from: variation in RNA-Seq transcriptome profiles of peripheral whole blood from healthy individuals with and without globin depletion. Gene expression omnibus (GEO), series GSE53655. Available: https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE53655 [Accessed 15 May 2019]."},{"key":"2026061204451530000_63.3.164.30","unstructured":"Weidinger S , Rodriguez E , Tsoi LC , et al . Data from: atopic dermatitis, psoriasis and healthy control RNA-seq cohort. Gene expression omnibus (GEO), series GSE121212. 2023. Available: https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE121212"},{"key":"2026061204451530000_63.3.164.31","unstructured":"Andrews S . FastQC: a quality control tool for high throughput sequence data. 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RNA mis-splicing in children with myotonic dystrophy is associated with physical function. bioRxiv 2024:2024.07.03.600889. doi:10.1101\/2024.07.03.600889","DOI":"10.1101\/2024.07.03.600889"},{"key":"2026061204451530000_63.3.164.42","doi-asserted-by":"crossref","DOI":"10.3390\/genes11091109","article-title":"An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I","volume":"11","author":"L\u00f3pez-Mart\u00ednez","year":"2020","journal-title":"Genes (Basel)"},{"key":"2026061204451530000_63.3.164.43","doi-asserted-by":"publisher","DOI":"10.2174\/138920208786847944"},{"key":"2026061204451530000_63.3.164.44","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms11067","article-title":"Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy","volume":"7","author":"Freyermuth","year":"2016","journal-title":"Nat Commun"},{"key":"2026061204451530000_63.3.164.45","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-023-37619-1","article-title":"Correction of Clcn1 alternative splicing reverses muscle fiber type transition in mice with myotonic dystrophy","volume":"14","author":"Hu","year":"2023","journal-title":"Nat Commun"},{"key":"2026061204451530000_63.3.164.46","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(02)00563-4"},{"key":"2026061204451530000_63.3.164.47","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2374"},{"key":"2026061204451530000_63.3.164.48","doi-asserted-by":"publisher","DOI":"10.1126\/science.280.5364.737"},{"key":"2026061204451530000_63.3.164.49","doi-asserted-by":"publisher","DOI":"10.1038\/ng704"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg-2025-110919","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T11:45:59Z","timestamp":1781264759000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg-2025-110919"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,28]]},"references-count":49,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2,20]]},"published-print":{"date-parts":[[2026,3]]}},"alternative-id":["10.1136\/jmg-2025-110919"],"URL":"https:\/\/doi.org\/10.1136\/jmg-2025-110919","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,28]]}}}