{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T13:38:56Z","timestamp":1790257136262,"version":"4.1.0"},"reference-count":36,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,3,23]],"date-time":"2020-03-23T00:00:00Z","timestamp":1584921600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007393","name":"Association Fran\u00e7aise contre les Myopathies","doi-asserted-by":"publisher","award":["10906"],"award-info":[{"award-number":["10906"]}],"id":[{"id":"10.13039\/100007393","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Molecular defects in type 1 facioscapulohumeral muscular dystrophy (FSHD) are caused by a heterozygous contraction of the D4Z4 repeat array from 1 to 10 repeat units (RUs) on 4q35. This study compared (1) the phenotype and severity of FSHD1 between patients carrying 6\u20138 vs. 9\u201310 RUs, (2) the amount of methylation in different D4Z4 regions between patients with FSHD1 with different clinical severity scores (CSS). This cross-sectional multicenter study was conducted to measure functional scales and for genetic analysis. Patients were classified into two categories according to RUs: Group 1, 6\u20138; Group 2, 9\u201310. Methylation analysis was performed in 27 patients. A total of 99 carriers of a contracted D4Z4 array were examined. No significant correlations between RUs and CSS (r = 0.04, p = 0.73) and any of the clinical outcome scales were observed between the two groups. Hypomethylation was significantly more pronounced in patients with high CSS (&gt;3.5) than those with low CSS (&lt;1.5) (in DR1 and 5P), indicating that the extent of hypomethylation might modulate disease severity. In Group 1, the disease severity is not strongly correlated with the allele size and is mostly correlated with the methylation of D4Z4 regions.<\/jats:p>","DOI":"10.3390\/ijms21062221","type":"journal-article","created":{"date-parts":[[2020,3,24]],"date-time":"2020-03-24T07:16:08Z","timestamp":1585034168000},"page":"2221","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Type 1 FSHD with 6\u201310 Repeated Units: Factors Underlying Severity in Index Cases and Disease Penetrance in Their Relatives Attention"],"prefix":"10.3390","volume":"21","author":[{"given":"Emmanuelle","family":"Salort-Campana","sequence":"first","affiliation":[{"name":"Reference Center of Neuromuscular disorders and ALS, Timone University Hospital, AP-HM, 264 rue Saint-Pierre, Cedex 05 13385 Marseille, France"},{"name":"Medical Genetics, Aix Marseille Universit\u00e9\u2014Inserm UMR_1251, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6774-7825","authenticated-orcid":false,"given":"Farzad","family":"Fatehi","sequence":"additional","affiliation":[{"name":"Reference Center of Neuromuscular disorders and ALS, Timone University Hospital, AP-HM, 264 rue Saint-Pierre, Cedex 05 13385 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadia","family":"Beloribi-Djefaflia","sequence":"additional","affiliation":[{"name":"Reference Center of Neuromuscular disorders and ALS, Timone University Hospital, AP-HM, 264 rue Saint-Pierre, Cedex 05 13385 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Roche","sequence":"additional","affiliation":[{"name":"Medical Genetics, Aix Marseille Universit\u00e9\u2014Inserm UMR_1251, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Medical Genetics, Aix Marseille Universit\u00e9\u2014Inserm UMR_1251, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafaelle","family":"Bernard","sequence":"additional","affiliation":[{"name":"Medical Genetics, Aix Marseille Universit\u00e9\u2014Inserm UMR_1251, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0242-4849","authenticated-orcid":false,"given":"Pascal","family":"Cintas","sequence":"additional","affiliation":[{"name":"Service de Neurologie et d\u2019explorations fonctionnelles, Centre Hospitalier Universitaire de Toulouse, 31000 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9599-6573","authenticated-orcid":false,"given":"Guilhem","family":"Sol\u00e9","sequence":"additional","affiliation":[{"name":"Reference Center of Neuromuscular Disorders AOC, Bordeaux University Hospitals, 33000 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7oise","family":"Bouhour","sequence":"additional","affiliation":[{"name":"Electroneuromyography and Neuromuscular Department, GHE Neurologic Hospital, Cedex 69677 Lyon-Bron, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Ollagnon","sequence":"additional","affiliation":[{"name":"Neurogenetic Department, GHN Croix-Rousse Hospital, 69004 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Sacconi","sequence":"additional","affiliation":[{"name":"Neuromuscular Disease Specialized Center, Nice University Hospital, 06000 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andoni","family":"Echaniz-Laguna","sequence":"additional","affiliation":[{"name":"Neurology Department, APHP, CHU de Bic\u00eatre, 78 rue du G\u00e9n\u00e9ral Leclerc, Cedex 94276 Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7788-1673","authenticated-orcid":false,"given":"Thierry","family":"Kuntzer","sequence":"additional","affiliation":[{"name":"Nerve-Muscle Unit, Department of Clinical Neurosciences, Lausanne University, Hospital (CHUV), Lausanne 1002, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Levy","sequence":"additional","affiliation":[{"name":"Medical Genetics, Aix Marseille Universit\u00e9\u2014Inserm UMR_1251, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0159-9559","authenticated-orcid":false,"given":"Fr\u00e9d\u00e9rique","family":"Magdinier","sequence":"additional","affiliation":[{"name":"Medical Genetics, Aix Marseille Universit\u00e9\u2014Inserm UMR_1251, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahram","family":"Attarian","sequence":"additional","affiliation":[{"name":"Reference Center of Neuromuscular disorders and ALS, Timone University Hospital, AP-HM, 264 rue Saint-Pierre, Cedex 05 13385 Marseille, France"},{"name":"Medical Genetics, Aix Marseille Universit\u00e9\u2014Inserm UMR_1251, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1126\/science.1189044","article-title":"A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy","volume":"329","author":"Lemmers","year":"2010","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/0960-8966(91)90094-9","article-title":"Diagnostic criteria for facioscapulohumeral muscular dystrophy","volume":"1","author":"Padberg","year":"1991","journal-title":"Neuromuscul. Disord."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.nmd.2010.04.007","article-title":"171st ENMC International Workshop: Standards of care and management of facioscapulohumeral muscular dystrophy","volume":"20","author":"Tawil","year":"2010","journal-title":"Neuromuscul. Disord."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1212\/WNL.0000000000000797","article-title":"Population-based incidence and prevalence of facioscapulohumeral dystrophy","volume":"83","author":"Deenen","year":"2014","journal-title":"Neurology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1111\/j.1399-0004.2009.01158.x","article-title":"Facioscapulohumeral muscular dystrophy: epidemiological and molecular study in a north-east Italian population sample","volume":"75","author":"Mostacciuolo","year":"2009","journal-title":"Clin. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1093\/hmg\/ddu536","article-title":"Direct interplay between two candidate genes in FSHD muscular dystrophy","volume":"24","author":"Ferri","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_7","first-page":"396","article-title":"Regional mapping of facioscapulohumeral muscular dystrophy gene on 4q35: Combined analysis of an international consortium","volume":"51","author":"Sarfarazi","year":"1992","journal-title":"Am. J. Hum. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Feeney, S.J., McGrath, M.J., Sriratana, A., Gehrig, S.M., Lynch, G.S., D\u2019Arcy, C.E., Price, J.T., McLean, C.A., Tupler, R., and Mitchell, C.A. (2015). FHL1 Reduces Dystrophy in Transgenic Mice Overexpressing FSHD Muscular Dystrophy Region Gene 1 (FRG1). PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0117665"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1097\/WCO.0b013e328357f22d","article-title":"Facioscapulohumeral muscular dystrophy: consequences of chromatin relaxation","volume":"25","author":"Miller","year":"2012","journal-title":"Curr. Opin. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/jhg.2012.74","article-title":"Deciphering transcription dysregulation in FSH muscular dystrophy","volume":"57","author":"Ehrlich","year":"2012","journal-title":"J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1212\/WNL.0000000000002217","article-title":"Milder phenotype in facioscapulohumeral dystrophy with 7\u201310 residual D4Z4 repeats","volume":"85","author":"Statland","year":"2015","journal-title":"Neurology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3408","DOI":"10.1093\/brain\/awt226","article-title":"Large scale genotype-phenotype analyses indicate that novel prognostic tools are required for families with facioscapulohumeral muscular dystrophy","volume":"136","author":"Ricci","year":"2013","journal-title":"Brain"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e007798","DOI":"10.1136\/bmjopen-2015-007798","article-title":"Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1\u20133 D4Z4 reduced alleles: experience of the FSHD Italian National Registry","volume":"6","author":"Nikolic","year":"2016","journal-title":"BMJ Open"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1016\/j.ajhg.2012.02.019","article-title":"Large-Scale Population Analysis Challenges the Current Criteria for the Molecular Diagnosis of Fascioscapulohumeral Muscular Dystrophy","volume":"90","author":"Scionti","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.gde.2015.08.007","article-title":"Genetic and epigenetic contributors to FSHD","volume":"33","author":"Daxinger","year":"2015","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1212\/WNL.0000000000000708","article-title":"Differential DNA methylation of the D4Z4 repeat in patients with FSHD and asymptomatic carriers","volume":"83","author":"Gaillard","year":"2014","journal-title":"Neurology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1016\/j.ajhg.2013.08.004","article-title":"The FSHD2 Gene SMCHD1 Is a Modifier of Disease Severity in Families Affected by FSHD1","volume":"93","author":"Sacconi","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13023-014-0218-1","article-title":"Low penetrance in facioscapulohumeral muscular dystrophy type 1 with large pathological D4Z4 alleles: a cross-sectional multicenter study","volume":"10","author":"Emmanuelle","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e372","DOI":"10.1212\/NXG.0000000000000372","article-title":"Methylation hotspots evidenced by deep sequencing in patients with facioscapulohumeral dystrophy and mosaicism","volume":"5","author":"Roche","year":"2019","journal-title":"Neurol. Genet."},{"key":"ref_20","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":"ref_21","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1002\/ana.410390610","article-title":"The Fsh-Dy Group Evidence for anticipation and association of deletion size with severity in facioscapulohumerd muscular dystrophy","volume":"39","author":"Tawil","year":"1996","journal-title":"Ann. Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"S103","DOI":"10.1002\/mus.880181319","article-title":"Phenotypic-genotypic correlation will assist genetic counseling in 4q35-facioscapulohumeral muscular dystrophy","volume":"18","author":"Lunt","year":"1995","journal-title":"Muscle Nerve"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/0960-8966(94)00055-E","article-title":"DNA rearrangements in Japanese facioscapulohumeral muscular dystrophy patients: clinical correlations","volume":"5","author":"Goto","year":"1995","journal-title":"Neuromuscul. Disord."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1001\/archneur.1994.00540160085011","article-title":"Facioscapulohumeral Muscular Dystrophy in Early Childhood","volume":"51","author":"Brouwer","year":"1994","journal-title":"Arch. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.nmd.2011.11.001","article-title":"Mutation spectrum and phenotypic manifestation in FSHD Greek patients","volume":"22","author":"Sakellariou","year":"2012","journal-title":"Neuromuscul. Disord."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/j.nmd.2008.06.387","article-title":"Becker\u2019s muscular dystrophy aggravating facioscapulohumeral muscular dystrophy\u2013double trouble as an explanation for an atypical phenotype","volume":"18","author":"Weis","year":"2008","journal-title":"Neuromuscul. Disord."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.nmd.2008.03.011","article-title":"Phenotype of combined Duchenne and facioscapulohumeral muscular dystrophy","volume":"18","author":"Korngut","year":"2008","journal-title":"Neuromuscul. Disord."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.4103\/0366-6999.159336","article-title":"New Insights into Genotype-phenotype Correlations in Chinese Facioscapulohumeral Muscular Dystrophy: A Retrospective Analysis of 178 Patients","volume":"128","author":"Lin","year":"2015","journal-title":"Chin. Med. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2822","DOI":"10.1093\/nar\/gkz005","article-title":"SMCHD1 is involved in de novo methylation of the DUX4-encoding D4Z4 macrosatellite","volume":"47","author":"Dion","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.tig.2017.01.007","article-title":"The Epigenetic Regulator SMCHD1 in Development and Disease","volume":"33","author":"Jansz","year":"2017","journal-title":"Trends Genet."},{"key":"ref_31","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":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.mrfmmm.2008.07.011","article-title":"Epigenetic mechanisms of facioscapulohumeral muscular dystrophy","volume":"647","author":"Frants","year":"2008","journal-title":"Mutat. Res. Mol. Mech. Mutagen."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"B\u00e9rard, C., Payan, C., Hodgkinson, I., and Fermanian, J. (2005). A motor function measure for neuromuscular diseases. Construction and validation study. Neuromuscul. Disord., 15.","DOI":"10.1016\/j.nmd.2005.03.004"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1002\/mus.880040304","article-title":"Clinical trial in duchenne dystrophy. I. The design of the protocol","volume":"4","author":"Brooke","year":"1981","journal-title":"Muscle Nerve"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/0021-9681(60)90105-3","article-title":"Maintenance of ambulation in childhood muscular dystrophy","volume":"12","author":"Vignos","year":"1960","journal-title":"J. Chronic Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1212\/WNL.0b013e31827f075c","article-title":"A focal domain of extreme demethylation within D4Z4 in FSHD2","volume":"80","author":"Hartweck","year":"2013","journal-title":"Neurology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/6\/2221\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:10:49Z","timestamp":1760173849000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/6\/2221"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,23]]},"references-count":36,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["ijms21062221"],"URL":"https:\/\/doi.org\/10.3390\/ijms21062221","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,23]]}}}