{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:10:47Z","timestamp":1791317447579,"version":"4.3.1"},"reference-count":21,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T00:00:00Z","timestamp":1751932800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T00:00:00Z","timestamp":1751932800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Hum Genet"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The size of non-pathogenic CTG repeats in the 3\u2019UTR of the\n                    <jats:italic>DMPK<\/jats:italic>\n                    gene varies from 5\u201335, whereas repeats over 50 units are pathogenic. The Intermediate repeats of 36\u201350 are considered \u2018premutation\u2019, as they are present in individuals unaffected by myotonic dystrophy, but are prone to further enlargement into the pathogenic range upon transmission to offspring. In this study, we showed that CCGCTG interrupted intermediate repeats, in the repeat size of 37\u201343 units, have been detected in multiple families with a history of myotonic dystrophy. However, segregation and microsatellite marker analysis of these interrupted intermediate alleles revealed that these alleles are not the same alleles (haplotypes) that were found expanded in affected family members. In contrast to the pure intermediate alleles, the CCGCTG intermediate repeats within families did not show intergenerational variability in size. Furthermore, we showed that the CCGCTG interrupted intermediate alleles have an allele frequency of approximately 0.35% in the general population, while CCGCTG interruptions were not detected in pathogenic repeat expansions over 50 repeat units in our control cohort. We postulate that intermediate repeats of size 37\u201343 having CCGCTG interruptions are not prone to further expansion, and therefore not act as premutations, which has great relevance for individuals with these alleles and has implications for genetic counseling and testing.\n                  <\/jats:p>","DOI":"10.1038\/s41431-025-01907-9","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T20:53:59Z","timestamp":1751921639000},"page":"1547-1553","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Interrupted CTG repeats in the 37\u201343 units size range in the 3\u02b9UTR of DMPK are common alleles"],"prefix":"10.1038","volume":"33","author":[{"given":"Hilde","family":"Swinkels","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maike","family":"Leferink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5485-7497","authenticated-orcid":false,"given":"Maartje","family":"Pennings","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0546-1351","authenticated-orcid":false,"given":"Bart","family":"van der Sanden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1693-9699","authenticated-orcid":false,"given":"Christian","family":"Gilissen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi Corominas","family":"Galbany","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6480-1892","authenticated-orcid":false,"given":"Erik-Jan","family":"Kamsteeg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,8]]},"reference":[{"key":"1907_CR1","doi-asserted-by":"publisher","first-page":"1599","DOI":"10.1007\/s10072-024-07826-9","volume":"46","author":"M Rimoldi","year":"2025","unstructured":"Rimoldi M, Lucchiari S, Pagliarani S, Meola G, Comi GP, Abati E. Myotonic dystrophies: an update on clinical features, molecular mechanisms, management, and gene therapy. Neurol Sci. 2025;46:1599\u2013616.","journal-title":"Neurol Sci"},{"key":"1907_CR2","unstructured":"Bird, TD Myotonic Dystrophy Type 1. In: Adam MP, Ardinger HH, Pagon RA et al. (eds). GeneReviews((R)) Seattle (WA), 1993."},{"key":"1907_CR3","doi-asserted-by":"crossref","unstructured":"Moxley III, RT, Hilbert, JE, Meoli, G The myotonic dystrophies. In: Rosenberg RN, Pascual JM (eds). Rosenberg\u2019s molecular and genetic basis of neurological and psychiatric disease.7th edn. Elsevier, Academic Press, London, United Kingdom, 2025, Vol 2, pp 613-28.","DOI":"10.1016\/B978-0-443-19176-3.00029-7"},{"key":"1907_CR4","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1159\/000524734","volume":"56","author":"Q Liao","year":"2022","unstructured":"Liao Q, Zhang Y, He J, Huang K. Global prevalence of myotonic dystrophy: an updated systematic review and meta-analysis. Neuroepidemiology. 2022;56:163\u201373.","journal-title":"Neuroepidemiology"},{"key":"1907_CR5","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1136\/jmg.38.12.846","volume":"38","author":"S Fokstuen","year":"2001","unstructured":"Fokstuen S, Myring J, Evans C, Harper PS. Presymptomatic testing in myotonic dystrophy: genetic counselling approaches. J Med Genet. 2001;38:846\u201350.","journal-title":"J Med Genet"},{"key":"1907_CR6","doi-asserted-by":"crossref","unstructured":"New nomenclature and DNA testing guidelines for myotonic dystrophy type 1 (DM1). The International Myotonic Dystrophy Consortium (IDMC). Neurology. 2000; 54:1218-21.","DOI":"10.1212\/WNL.54.6.1218"},{"key":"1907_CR7","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1212\/WNL.56.3.328","volume":"56","author":"L Martorell","year":"2001","unstructured":"Martorell L, Monckton DG, Sanchez A, Lopez De Munain A, Baiget M. Frequency and stability of the myotonic dystrophy type 1 premutation. Neurology. 2001;56:328\u201335.","journal-title":"Neurology"},{"key":"1907_CR8","doi-asserted-by":"publisher","first-page":"1365","DOI":"10.1002\/ajmg.a.32987","volume":"149A","author":"Z Musova","year":"2009","unstructured":"Musova Z, Mazanec R, Krepelova A, Ehler E, Vales J, Jaklova R, et al. Highly unstable sequence interruptions of the CTG repeat in the myotonic dystrophy gene. Am J Med Genet A. 2009;149A:1365\u201374.","journal-title":"Am J Med Genet A"},{"key":"1907_CR9","doi-asserted-by":"publisher","first-page":"1399","DOI":"10.1093\/hmg\/ddq015","volume":"19","author":"C Braida","year":"2010","unstructured":"Braida C, Stefanatos RK, Adam B, Mahajan N, Smeets HJ, Niel F, et al. Variant CCG and GGC repeats within the CTG expansion dramatically modify mutational dynamics and likely contribute toward unusual symptoms in some myotonic dystrophy type 1 patients. Hum Mol Genet. 2010;19:1399\u2013412.","journal-title":"Hum Mol Genet"},{"key":"1907_CR10","doi-asserted-by":"publisher","first-page":"457","DOI":"10.3390\/ijms21020457","volume":"21","author":"S Tome","year":"2020","unstructured":"Tome S, Gourdon G. DM1 phenotype variability and triplet repeat instability: challenges in the development of new therapies. Int J Mol Sci. 2020;21:457.","journal-title":"Int J Mol Sci"},{"key":"1907_CR11","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1128\/MCB.20.1.173-180.2000","volume":"20","author":"ML Rolfsmeier","year":"2000","unstructured":"Rolfsmeier ML, Lahue RS. Stabilizing effects of interruptions on trinucleotide repeat expansions in Saccharomyces cerevisiae. Molecular Cell Biol. 2000;20:173\u201380.","journal-title":"Molecular Cell Biol"},{"key":"1907_CR12","doi-asserted-by":"publisher","first-page":"1635","DOI":"10.1038\/s41431-018-0156-9","volume":"26","author":"SA Cumming","year":"2018","unstructured":"Cumming SA, Hamilton MJ, Robb Y, Gregory H, McWilliam C, Cooper A, et al. De novo repeat interruptions are associated with reduced somatic instability and mild or absent clinical features in myotonic dystrophy type 1. Eur J Hum Genet. 2018;26:1635\u201347.","journal-title":"Eur J Hum Genet"},{"key":"1907_CR13","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1093\/hmg\/4.1.135","volume":"4","author":"EP Leeflang","year":"1995","unstructured":"Leeflang EP, Arnheim N. A novel repeat structure at the myotonic dystrophy locus in a 37 repeat allele with unexpectedly high stability. Hum Mol Genet. 1995;4:135\u20136.","journal-title":"Hum Mol Genet"},{"key":"1907_CR14","doi-asserted-by":"publisher","first-page":"1569","DOI":"10.1038\/s41436-021-01174-1","volume":"23","author":"B van der Sanden","year":"2021","unstructured":"van der Sanden B, Corominas J, de Groot M, Pennings M, Meijer RPP, Verbeek N, et al. Systematic analysis of short tandem repeats in 38,095 exomes provides an additional diagnostic yield. Genet Med. 2021;23:1569\u201373.","journal-title":"Genet Med"},{"key":"1907_CR15","doi-asserted-by":"publisher","first-page":"e1619","DOI":"10.1002\/mgg3.1619","volume":"9","author":"RJ Butterfield","year":"2021","unstructured":"Butterfield RJ, Imburgia C, Mayne K, Newcomb T, Dunn DM, Duval B, et al. High throughput screening for expanded CTG repeats in myotonic dystrophy type 1 using melt curve analysis. Mol Genet Genom Med. 2021;9:e1619.","journal-title":"Mol Genet Genom Med"},{"key":"1907_CR16","doi-asserted-by":"publisher","first-page":"3357","DOI":"10.1038\/s41591-024-03190-5","volume":"30","author":"K Ibanez","year":"2024","unstructured":"Ibanez K, Jadhav B, Zanovello M, Gagliardi D, Clarkson C, Facchini S, et al. Increased frequency of repeat expansion mutations across different populations. Nat Med. 2024;30:3357\u201368.","journal-title":"Nat Med"},{"key":"1907_CR17","doi-asserted-by":"publisher","first-page":"956","DOI":"10.1038\/s41431-020-0601-4","volume":"28","author":"IBT Joosten","year":"2020","unstructured":"Joosten IBT, Hellebrekers D, de Greef BTA, Smeets HJM, de Die-Smulders CEM, Faber CG, et al. Parental repeat length instability in myotonic dystrophy type 1 pre- and protomutations. Eur J Hum Genet. 2020;28:956\u201362.","journal-title":"Eur J Hum Genet"},{"key":"1907_CR18","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1038\/ejhg.2016.148","volume":"25","author":"A Botta","year":"2017","unstructured":"Botta A, Rossi G, Marcaurelio M, Fontana L, D\u2019Apice MR, Brancati F, et al. Identification and characterization of 5\u2019 CCG interruptions in complex DMPK expanded alleles. Eur J Hum Genet. 2017;25:257\u201361.","journal-title":"Eur J Hum Genet"},{"key":"1907_CR19","doi-asserted-by":"publisher","first-page":"1188","DOI":"10.1038\/ejhg.2010.10","volume":"18","author":"J Sequeiros","year":"2010","unstructured":"Sequeiros J, Seneca S, Martindale J. Consensus and controversies in best practices for molecular genetic testing of spinocerebellar ataxias. Eur J Hum Genet. 2010;18:1188\u201395.","journal-title":"Eur J Hum Genet"},{"key":"1907_CR20","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1002\/ajmg.a.35833","volume":"161A","author":"SL Nolin","year":"2013","unstructured":"Nolin SL, Sah S, Glicksman A, Sherman SL, Allen E, Berry-Kravis E, et al. Fragile X AGG analysis provides new risk predictions for 45-69 repeat alleles. Am J Med Genet A. 2013;161A:771\u20138.","journal-title":"Am J Med Genet A"},{"key":"1907_CR21","doi-asserted-by":"publisher","first-page":"354","DOI":"10.3390\/ijms23010354","volume":"23","author":"S Peric","year":"2021","unstructured":"Peric S, Pesovic J, Savic-Pavicevic D, Rakocevic Stojanovic V, Meola G. Molecular and clinical implications of variant repeats in myotonic dystrophy type 1. Int J Mol Sci. 2021;23:354.","journal-title":"Int J Mol Sci"}],"container-title":["European Journal of Human Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41431-025-01907-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41431-025-01907-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41431-025-01907-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T09:00:50Z","timestamp":1762160450000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41431-025-01907-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,8]]},"references-count":21,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2025,11]]}},"alternative-id":["1907"],"URL":"https:\/\/doi.org\/10.1038\/s41431-025-01907-9","relation":{},"ISSN":["1018-4813","1476-5438"],"issn-type":[{"value":"1018-4813","type":"print"},{"value":"1476-5438","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,8]]},"assertion":[{"value":"12 December 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 June 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 June 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 July 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Diagnostic laboratories can use (de-identified) samples from archived clinical samples to validate and optimize diagnostic assays. Therefore, the individuals in the pedigrees are shown without information about age or other identifiers. Where necessary, the sex is shown, other individuals are indicated by diamonds. These methods are also in accordance with relevant guidelines and regulations and approved by the institutional review board of the Radboud University Medical Center (2020-7142) and the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}