{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T17:07:30Z","timestamp":1779124050717,"version":"3.51.4"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2021,9,24]],"date-time":"2021-09-24T00:00:00Z","timestamp":1632441600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100004243","name":"Prinses Beatrix Spierfonds","doi-asserted-by":"publisher","award":["W.OB17-01"],"award-info":[{"award-number":["W.OB17-01"]}],"id":[{"id":"10.13039\/501100004243","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004243","name":"Prinses Beatrix Spierfonds","doi-asserted-by":"publisher","award":["W.OP14-01"],"award-info":[{"award-number":["W.OP14-01"]}],"id":[{"id":"10.13039\/501100004243","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["P01NS069539"],"award-info":[{"award-number":["P01NS069539"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,3,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Facioscapulohumeral muscular dystrophy (FSHD) is an inherited myopathy clinically characterized by weakness in the facial, shoulder girdle and upper a muscles. FSHD is caused by chromatin relaxation of the D4Z4 macrosatellite repeat, mostly by a repeat contraction, facilitating ectopic expression of DUX4 in skeletal muscle. Genetic diagnosis for FSHD is generally based on the sizing and haplotyping of the D4Z4 repeat on chromosome 4 by Southern blotting (SB), molecular combing or single-molecule optical mapping, which is usually straight forward but can be complicated by atypical rearrangements of the D4Z4 repeat. One of these rearrangements is a D4Z4 proximally extended deletion (DPED) allele, where not only the D4Z4 repeat is partially deleted, but also sequences immediately proximal to the repeat are lost, which can impede accurate diagnosis in all genetic methods. Previously, we identified several DPED alleles in FSHD and estimated the size of the proximal deletions by a complex pulsed-field gel electrophoresis and SB strategy. Here, using the next-generation sequencing, we have defined the breakpoint junctions of these DPED alleles at the base pair resolution in 12 FSHD families and 4 control individuals facilitating a PCR-based diagnosis of these DPED alleles. Our resultsshow that half of the DPED alleles are derivates of an ancient founder allele. For some DPED alleles, we found that genetic elements are deleted such as DUX4c, FRG2, DBE-T and myogenic enhancers necessitating re-evaluation of their role in FSHD pathogenesis.<\/jats:p>","DOI":"10.1093\/hmg\/ddab250","type":"journal-article","created":{"date-parts":[[2021,9,23]],"date-time":"2021-09-23T21:40:51Z","timestamp":1632433251000},"page":"748-760","source":"Crossref","is-referenced-by-count":17,"title":["High-resolution breakpoint junction mapping of proximally extended D4Z4 deletions in FSHD1 reveals evidence for a founder effect"],"prefix":"10.1093","volume":"31","author":[{"given":"Richard J L F","family":"Lemmers","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick J","family":"van der Vliet","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David San Leon","family":"Granado","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nienke","family":"van der Stoep","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henk","family":"Buermans","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robin","family":"van Schendel","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joost","family":"Schimmel","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marianne","family":"de Visser","sequence":"additional","affiliation":[{"name":"Department of Neurology, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rudy","family":"van Coster","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Neurology, Ghent University Hospital, Ghent, 9000, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc","family":"Jeanpierre","sequence":"additional","affiliation":[{"name":"APHP-H\u00f4pitaux de Paris, Universit\u00e9 de Paris, Paris, 75400, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pascal","family":"Laforet","sequence":"additional","affiliation":[{"name":"Neurology Department, Raymond-Poincar\u00e9 Hospital, Garches, 92380, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meena","family":"Upadhyaya","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Cardiff University, Cardiff, CF10 3AT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baziel","family":"van Engelen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, 6500 HB, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"Sacconi","sequence":"additional","affiliation":[{"name":"Centre de r\u00e9f\u00e9rence des Maladies neuromusculaires, Nice University Hospital, Nice, 06000, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rabi","family":"Tawil","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Rochester Medical Center, Rochester, NY, NY 14642, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicol C","family":"Voermans","sequence":"additional","affiliation":[{"name":"Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, 6500 HB, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Rogers","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Cardiff University, Cardiff, CF10 3AT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silv\u00e8re M","family":"van der Maarel","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,9,24]]},"reference":[{"key":"2022030413202311500_ref1","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1136\/practneurol-2015-001353","article-title":"What's in a name? 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Genet."},{"key":"2022030413202311500_ref5","doi-asserted-by":"crossref","first-page":"5901","DOI":"10.1093\/hmg\/ddv315","article-title":"Endogenous DUX4 expression in FSHD myotubes is sufficient to cause cell death and disrupts RNA splicing and cell migration pathways","volume":"24","author":"Rickard","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"2022030413202311500_ref6","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1080\/15592294.2015.1113798","article-title":"Increased DUX4 expression during muscle differentiation correlates with decreased SMCHD1 protein levels at D4Z4","volume":"10","author":"Balog","year":"2015","journal-title":"Epigenetics"},{"key":"2022030413202311500_ref7","doi-asserted-by":"crossref","first-page":"5342","DOI":"10.1093\/hmg\/ddu251","article-title":"DUX4-induced gene expression is the major molecular signature in FSHD skeletal muscle","volume":"23","author":"Yao","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"2022030413202311500_ref8","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1038\/ng.3844","article-title":"Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL\/HERVL retrotransposons","volume":"49","author":"Hendrickson","year":"2017","journal-title":"Nat. Genet."},{"key":"2022030413202311500_ref9","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1038\/ng.3846","article-title":"Conservation and innovation in the DUX4-family gene network","volume":"49","author":"Whiddon","year":"2017","journal-title":"Nat. Genet."},{"key":"2022030413202311500_ref10","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1038\/ng.3858","article-title":"DUX-family transcription factors regulate zygotic genome activation in placental mammals","volume":"49","author":"De Iaco","year":"2017","journal-title":"Nat. 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Genet."},{"key":"2022030413202311500_ref23","doi-asserted-by":"crossref","first-page":"e2441","DOI":"10.1212\/WNL.0000000000009617","article-title":"Homozygous nonsense variant in LRIF1 associated with facioscapulohumeral muscular dystrophy","volume":"94","author":"Hamanaka","year":"2020","journal-title":"Neurology"},{"key":"2022030413202311500_ref24","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1038\/ng.2454","article-title":"Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2","volume":"44","author":"Lemmers","year":"2012","journal-title":"Nat. Genet."},{"key":"2022030413202311500_ref25","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1016\/j.ajhg.2016.03.013","article-title":"Mutations in DNMT3B modify epigenetic repression of the D4Z4 repeat and the penetrance of facioscapulohumeral dystrophy","volume":"98","author":"Boogaard","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"2022030413202311500_ref26","doi-asserted-by":"crossref","first-page":"e2273","DOI":"10.1212\/WNL.0000000000007456","article-title":"FSHD1 and FSHD2 form a disease continuum","volume":"92","author":"Sacconi","year":"2019","journal-title":"Neurology"},{"key":"2022030413202311500_ref27","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/978-1-4939-6442-0_7","article-title":"Analyzing copy number variation using pulsed-field gel electrophoresis: providing a genetic diagnosis for FSHD1","volume":"1492","author":"Lemmers","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"2022030413202311500_ref28","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1212\/01.wnl.0000254991.21818.f3","article-title":"Genotype-phenotype study in an FSHD family with a proximal deletion encompassing p13E-11 and D4Z4","volume":"68","author":"Deak","year":"2007","journal-title":"Neurology"},{"key":"2022030413202311500_ref29","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1212\/01.WNL.0000078889.51444.81","article-title":"D4F104S1 deletion in facioscapulohumeral muscular dystrophy: phenotype, size, and detection","volume":"61","author":"Lemmers","year":"2003","journal-title":"Neurology"},{"key":"2022030413202311500_ref30","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1093\/hmg\/7.8.1207","article-title":"Inter- and intrachromosomal subtelomeric rearrangements on 4q35: implications for facioscapulohumeral muscular dystrophy (FSHD) aetiology and diagnosis","volume":"7","author":"Lemmers","year":"1998","journal-title":"Hum. Mol. 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Genet."},{"key":"2022030413202311500_ref37","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s00412-006-0080-6","article-title":"Hybridization analysis of D4Z4 repeat arrays linked to FSHD","volume":"116","author":"Ehrlich","year":"2007","journal-title":"Chromosoma"},{"key":"2022030413202311500_ref38","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/j.cell.2012.03.035","article-title":"A long ncRNA links copy number variation to a polycomb\/trithorax epigenetic switch in FSHD muscular dystrophy","volume":"149","author":"Cabianca","year":"2012","journal-title":"Cell"},{"key":"2022030413202311500_ref39","doi-asserted-by":"crossref","first-page":"1942","DOI":"10.1128\/MCB.00149-14","article-title":"Myogenic enhancers regulate expression of the facioscapulohumeral muscular dystrophy-associated DUX4 gene","volume":"34","author":"Himeda","year":"2014","journal-title":"Mol. Cell. Biol."},{"key":"2022030413202311500_ref40","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13395-017-0148-4","article-title":"Overexpression of the double homeodomain protein DUX4c interferes with myofibrillogenesis and induces clustering of myonuclei","volume":"8","author":"Vanderplanck","year":"2018","journal-title":"Skelet. Muscle"},{"key":"2022030413202311500_ref41","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1136\/jmg.2004.019364","article-title":"FRG2, an FSHD candidate gene, is transcriptionally upregulated in differentiating primary myoblast cultures of FSHD patients","volume":"41","author":"Rijkers","year":"2004","journal-title":"J. Med. Genet."},{"key":"2022030413202311500_ref42","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/2044-5040-4-19","article-title":"DUX4 promotes transcription of FRG2 by directly activating its promoter in facioscapulohumeral muscular dystrophy","volume":"4","author":"Thijssen","year":"2014","journal-title":"Skelet. Muscle"},{"key":"2022030413202311500_ref43","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/s41431-017-0015-0","article-title":"Deep characterization of a common D4Z4 variant identifies biallelic DUX4 expression as a modifier for disease penetrance in FSHD2","volume":"26","author":"Lemmers","year":"2018","journal-title":"Eur. J. Hum. Genet."},{"key":"2022030413202311500_ref44","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1002\/1531-8249(199906)45:6<751::AID-ANA9>3.0.CO;2-M","article-title":"Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number of KpnI repeats at the 4q35 locus and clinical phenotype","volume":"45","author":"Ricci","year":"1999","journal-title":"Ann. Neurol."},{"key":"2022030413202311500_ref45","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1002\/ana.20625","article-title":"Variable hypomethylation of D4Z4 in facioscapulohumeral muscular dystrophy","volume":"58","author":"Overveld","year":"2005","journal-title":"Ann. Neurol."},{"key":"2022030413202311500_ref46","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/2044-5040-3-8","article-title":"Comparison of endogenous and overexpressed MyoD shows enhanced binding of physiologically bound sites","volume":"3","author":"Yao","year":"2013","journal-title":"Skelet. Muscle"},{"key":"2022030413202311500_ref47","article-title":"Chromosome 10q-linked FSHD identifies DUX4 as principal disease gene","author":"Lemmers","year":"2021","journal-title":"J. Med. Genet."},{"key":"2022030413202311500_ref48","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1093\/hmg\/ddu486","article-title":"Inter-individual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2","volume":"24","author":"Lemmers","year":"2015","journal-title":"Hum. Mol. 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