{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T14:07:10Z","timestamp":1790518030805,"version":"4.1.0"},"reference-count":35,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,4,10]],"date-time":"2020-04-10T00:00:00Z","timestamp":1586476800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GUP13012"],"award-info":[{"award-number":["GUP13012"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004923","name":"AFM-T\u00e9l\u00e9thon","doi-asserted-by":"publisher","award":["16593"],"award-info":[{"award-number":["16593"]}],"id":[{"id":"10.13039\/501100004923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009879","name":"Regione Emilia-Romagna","doi-asserted-by":"publisher","award":["RARER"],"award-info":[{"award-number":["RARER"]}],"id":[{"id":"10.13039\/501100009879","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01AR062587"],"award-info":[{"award-number":["R01AR062587"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Facioscapulohumeral muscular dystrophy (FSHD) is characterized by incomplete penetrance and intra-familial clinical variability. The disease has been associated with the genetic and epigenetic features of the D4Z4 repetitive elements at 4q35. Recently, D4Z4 hypomethylation has been proposed as a reliable marker in the FSHD diagnosis. We exploited the Italian Registry for FSHD, in which FSHD families are classified using the Clinical Comprehensive Evaluation Form (CCEF). A total of 122 index cases showing a classical FSHD phenotype (CCEF, category A) and 110 relatives were selected to test with the receiver operating characteristic (ROC) curve, the diagnostic and predictive value of D4Z4 methylation. Moreover, we performed DNA methylation analysis in selected large families with reduced penetrance characterized by the co-presence of subjects carriers of one D4Z4 reduced allele with no signs of disease or presenting the classic FSHD clinical phenotype. We observed a wide variability in the D4Z4 methylation levels among index cases revealing no association with clinical manifestation or disease severity. By extending the analysis to family members, we revealed the low predictive value of D4Z4 methylation in detecting the affected condition. In view of the variability in D4Z4 methylation profiles observed in our large cohort, we conclude that D4Z4 methylation does not mirror the clinical expression of FSHD. We recommend that measurement of this epigenetic mark must be interpreted with caution in clinical practice.<\/jats:p>","DOI":"10.3390\/ijms21072635","type":"journal-article","created":{"date-parts":[[2020,4,13]],"date-time":"2020-04-13T04:45:31Z","timestamp":1586753131000},"page":"2635","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Interpretation of the Epigenetic Signature of Facioscapulohumeral Muscular Dystrophy in Light of Genotype-Phenotype Studies"],"prefix":"10.3390","volume":"21","author":[{"given":"Ana","family":"Nikolic","sequence":"first","affiliation":[{"name":"Department of Science of Life, Institute of Biology, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takako I","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Nevada, Reno, NV 89557, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Govi","sequence":"additional","affiliation":[{"name":"Department of Science of Life, Institute of Biology, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiano","family":"Mele","sequence":"additional","affiliation":[{"name":"Center for Genome Research, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Maranda","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8890-6848","authenticated-orcid":false,"given":"Francesco","family":"Sera","sequence":"additional","affiliation":[{"name":"Department of Public Health, Environments and Society, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Ricci","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Neurological Clinic, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Ruggiero","sequence":"additional","affiliation":[{"name":"Department of Neurosciences and Reproductive and Odontostomatologic Sciences, University Federico II, 80137 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana","family":"Vercelli","sequence":"additional","affiliation":[{"name":"Department of Neurosciences \u201cRita Levi Montalcini\u201d, University of Turin, 10124 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6379-1642","authenticated-orcid":false,"given":"Simona","family":"Portaro","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mental Health and Sensory Organs, S. Andrea Hospital, University of Rome \u201cSapienza\u201d, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Villa","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Foundation IRCCS Ca\u2019 Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Fiorillo","sequence":"additional","affiliation":[{"name":"Pediatric Neurology and Neuromuscular Disorders Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16126 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0932-5173","authenticated-orcid":false,"given":"Lorenzo","family":"Maggi","sequence":"additional","affiliation":[{"name":"IRCCS Foundation, C. Besta Neurological Institute, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucio","family":"Santoro","sequence":"additional","affiliation":[{"name":"Department of Neurosciences and Reproductive and Odontostomatologic Sciences, University Federico II, 80137 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Antonini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mental Health and Sensory Organs, S. Andrea Hospital, University of Rome \u201cSapienza\u201d, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2852-7512","authenticated-orcid":false,"given":"Massimiliano","family":"Filosto","sequence":"additional","affiliation":[{"name":"Neurology Clinic, \u2018\u2018Spedali Civili\u2019\u2019. Hospital, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Moggio","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Foundation IRCCS Ca\u2019 Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9554-8794","authenticated-orcid":false,"given":"Corrado","family":"Angelini","sequence":"additional","affiliation":[{"name":"Ospedale S.Camillo IRCCS, Lido di Venezia, 20126 Venezia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Pegoraro","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, University of Padua, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Berardinelli","sequence":"additional","affiliation":[{"name":"Neurology and Psychiatry, IRCCS Institute \u2018C.Mondino\u2019 Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Antonetta","family":"Maioli","sequence":"additional","affiliation":[{"name":"ASL8, Centro Sclerosi Multipla, 09126 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grazia","family":"D\u2019Angelo","sequence":"additional","affiliation":[{"name":"Department of Neurorehabilitation, IRCCS Institute Eugenio Medea, 23842 Bosisio Parini, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonino","family":"Di Muzio","sequence":"additional","affiliation":[{"name":"Center for Neuromuscular Disease, CeSI, University \u2018\u2018G. D\u2019Annunzio\u2019\u2019, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Siciliano","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Neurological Clinic, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliano","family":"Tomelleri","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4783-7572","authenticated-orcid":false,"given":"Maurizio","family":"D\u2019Esposito","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics, A. Buzzati Traverso, IGB, Consiglio Nazionale delle Ricerche, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1643-6418","authenticated-orcid":false,"given":"Floriana","family":"Della Ragione","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics, A. Buzzati Traverso, IGB, Consiglio Nazionale delle Ricerche, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Brancaccio","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics, A. Buzzati Traverso, IGB, Consiglio Nazionale delle Ricerche, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachele","family":"Piras","sequence":"additional","affiliation":[{"name":"ASL8, Centro Sclerosi Multipla, 09126 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2543-6356","authenticated-orcid":false,"given":"Carmelo","family":"Rodolico","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Mongini","sequence":"additional","affiliation":[{"name":"Department of Neurosciences \u201cRita Levi Montalcini\u201d, University of Turin, 10124 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0159-9559","authenticated-orcid":false,"given":"Frederique","family":"Magdinier","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, INSERM, MMG, U 1251, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Salsi","sequence":"additional","affiliation":[{"name":"Department of Science of Life, Institute of Biology, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter L.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of Nevada, Reno, NV 89557, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3797-1789","authenticated-orcid":false,"given":"Rossella","family":"Tupler","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy"},{"name":"Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, 41125 Modena, Italy"},{"name":"Department of Molecular Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA"},{"name":"Li Weibo Institute for Rare Diseases Research at the University of Massachusetts Medical School, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,10]]},"reference":[{"key":"ref_1","unstructured":"Padberg, G.W.A.M. 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Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/7\/2635\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:17:12Z","timestamp":1760174232000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/7\/2635"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,10]]},"references-count":35,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["ijms21072635"],"URL":"https:\/\/doi.org\/10.3390\/ijms21072635","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,10]]}}}