{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T21:06:33Z","timestamp":1776287193660,"version":"3.50.1"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"23","license":[{"start":{"date-parts":[[2019,10,11]],"date-time":"2019-10-11T00:00:00Z","timestamp":1570752000000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health","award":["5X1000-2016"],"award-info":[{"award-number":["5X1000-2016"]}]},{"name":"Italian Ministry of Health","award":["5x2017 MINSAL.3"],"award-info":[{"award-number":["5x2017 MINSAL.3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>In this study, we investigated the sequence of (Structural Maintenance of Chromosomes flexible Hinge Domain containing 1) SMCHD1 gene in a cohort of clinically defined FSHD (facioscapulohumeral muscular dystrophy) patients in order to assess the distribution of SMCHD1 variants, considering the D4Z4 fragment size in terms of repeated units (RUs; short fragment: 1\u20137 RU, borderline: 8-10RU and normal fragment: &amp;gt;11RU). The analysis of SMCHD1 revealed the presence of 82 variants scattered throughout the introns, exons and 3\u2019untranslated region (3\u2032UTR) of the gene. Among them, 64 were classified as benign polymorphisms and 6 as VUS (variants of uncertain significance). Interestingly, seven pathogenic\/likely pathogenic variants were identified in patients carrying a borderline or normal D4Z4 fragment size, namely c.182_183dupGT (p.Q62Vfs*48), c.2129dupC (p.A711Cfs*11), c.3469G&amp;gt;T (p.G1157*), c.5150_5151delAA (p.K1717Rfs*16) and c.1131+2_1131+5delTAAG, c.3010A&amp;gt;T (p.K1004*), c.853G&amp;gt;C (p.G285R). All of them were predicted to disrupt the structure and conformation of SMCHD1, resulting in the loss of GHKL-ATPase and SMC hinge essential domains. These results are consistent with the FSHD symptomatology and the Clinical Severity Score (CSS) of patients. In addition, five variants (c.*1376A&amp;gt;C, rs7238459; c.*1579G&amp;gt;A, rs559994; c.*1397A&amp;gt;G, rs150573037; c.*1631C&amp;gt;T, rs193227855; c.*1889G&amp;gt;C, rs149259359) were identified in the 3\u2032UTR region of SMCHD1, suggesting a possible miRNA-dependent regulatory effect on FSHD-related pathways. The present study highlights the clinical utility of next-generation sequencing (NGS) platforms for the molecular diagnosis of FSHD and the importance of integrating molecular findings and clinical data in order to improve the accuracy of genotype\u2013phenotype correlations.<\/jats:p>","DOI":"10.1093\/hmg\/ddz239","type":"journal-article","created":{"date-parts":[[2019,10,3]],"date-time":"2019-10-03T15:26:17Z","timestamp":1570116377000},"page":"3912-3920","source":"Crossref","is-referenced-by-count":19,"title":["The variability of SMCHD1 gene in FSHD patients: evidence of new mutations"],"prefix":"10.1093","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1334-0920","authenticated-orcid":false,"given":"Claudia","family":"Strafella","sequence":"first","affiliation":[{"name":"Genomic Medicine Laboratory UILDM, Santa Lucia Foundation, Rome, 00142, Italy"},{"name":"Department of Biomedicine and Prevention, Tor Vergata University, Rome, 00133, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerio","family":"Caputo","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Prevention, Tor Vergata University, Rome, 00133, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosaria Maria","family":"Galota","sequence":"additional","affiliation":[{"name":"Genomic Medicine Laboratory UILDM, Santa Lucia Foundation, Rome, 00142, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia","family":"Campoli","sequence":"additional","affiliation":[{"name":"Genomic Medicine Laboratory UILDM, Santa Lucia Foundation, Rome, 00142, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Bax","sequence":"additional","affiliation":[{"name":"Genomic Medicine Laboratory UILDM, Santa Lucia Foundation, Rome, 00142, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Colantoni","sequence":"additional","affiliation":[{"name":"Genomic Medicine Laboratory UILDM, Santa Lucia Foundation, Rome, 00142, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulietta","family":"Minozzi","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine (DIMEVET), University of Milan, Milan, 20100, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Orsini","sequence":"additional","affiliation":[{"name":"vCardiomyology and Medical Genetics, Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, 80131, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luisa","family":"Politano","sequence":"additional","affiliation":[{"name":"vCardiomyology and Medical Genetics, Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, 80131, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giorgio","family":"Tasca","sequence":"additional","affiliation":[{"name":"Unit\u00e0 Operativa Complessa di Neurologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, 00168, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Novelli","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Prevention, Tor Vergata University, Rome, 00133, Italy"},{"name":"Neuromed Institute IRCCS, Pozzilli, 86077, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enzo","family":"Ricci","sequence":"additional","affiliation":[{"name":"Unit\u00e0 Operativa Complessa di Neurologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, 00168, Italy"},{"name":"Istituto di Neurologia, Universit\u00e0 Cattolica del Sacro Cuore, Rome, 00168, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emiliano","family":"Giardina","sequence":"additional","affiliation":[{"name":"Genomic Medicine Laboratory UILDM, Santa Lucia Foundation, Rome, 00142, Italy"},{"name":"Department of Biomedicine and Prevention, Tor Vergata University, Rome, 00133, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raffaella","family":"Cascella","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Prevention, Tor Vergata University, Rome, 00133, Italy"},{"name":"Department of Biomedical Sciences, Catholic University Our Lady of Good Counsel, Tirana, 1000, Albania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,10,10]]},"reference":[{"key":"2020011802263117100_ref1","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.preteyeres.2017.11.004","article-title":"Towards the application of precision medicine in age-related macular degeneration","volume":"63","author":"Cascella","year":"2018","journal-title":"Prog. Retin. Eye Res."},{"key":"2020011802263117100_ref2","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/s10048-019-00575-4","article-title":"Facioscapulohumeral muscular dystrophy (FSHD) molecular diagnosis: from traditional technology to the NGS era","volume":"20","author":"Zampatti","year":"2019","journal-title":"Neurogenetics"},{"key":"2020011802263117100_ref3","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1016\/j.mcna.2013.05.005","article-title":"Patients with neuromuscular disorder","volume":"97","author":"Turakhia","year":"2013","journal-title":"Med. Clin. North. Am."},{"key":"2020011802263117100_ref4","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.nmd.2005.10.001","article-title":"Facing the genetic heterogeneity in neuromuscular disorders: linkage analysis as an economic diagnostic approach towards the molecular diagnosis","volume":"16","author":"von der Hagen","year":"2006","journal-title":"Neuromuscul. Disord."},{"key":"2020011802263117100_ref5","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1186\/s12881-016-0328-9","article-title":"Segregation between SMCHD1 mutation, D4Z4 hypomethylation and facio-scapulo-humeral dystrophy: a case report","volume":"17","author":"Gaillard","year":"2016","journal-title":"BMC Med. Genet."},{"key":"2020011802263117100_ref6","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s13395-017-0129-7","article-title":"SMCHD1 regulates a limited set of gene clusters on autosomal chromosomes","volume":"7","author":"Mason","year":"2017","journal-title":"Skelet. Muscle"},{"key":"2020011802263117100_ref7","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.nmd.2018.01.001","article-title":"Genotype and phenotype analysis of 43 Iranian facioscapulohumeral muscular dystrophy patients; evidence for anticipation","volume":"28","author":"Alavi","year":"2018","journal-title":"Neuromuscul. Disord."},{"key":"2020011802263117100_ref8","first-page":"1916","article-title":"Facioscapulohumeral muscular dystrophy","volume":"22","author":"Statland","year":"2016","journal-title":"Continuum (MinneapMinn)."},{"key":"2020011802263117100_ref9","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1136\/practneurol-2015-001353","article-title":"What's in a name? The clinical features of facioscapulohumeral muscular dystrophy","volume":"16","author":"Mul","year":"2016","journal-title":"Pract. Neurol."},{"key":"2020011802263117100_ref10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0064691","article-title":"DUX4 differentially regulates transcriptomes of human rhabdomyosarcoma and mouse C2C12 cells","volume":"8","author":"Sharma","year":"2013","journal-title":"PLoS One."},{"key":"2020011802263117100_ref11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7554\/eLife.04996","article-title":"A feedback loop between nonsensemediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy","volume":"4","author":"Feng","year":"2015","journal-title":"eLife"},{"key":"2020011802263117100_ref12","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1212\/WNL.0b013e3181f96175","article-title":"Clinical features of facioscapulohumeral muscular dystrophy 2","volume":"75","author":"De Greef","year":"2010","journal-title":"Neurology"},{"key":"2020011802263117100_ref13","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.3389\/fpls.2017.01720","article-title":"MORC proteins: novel players in plant and animal health","volume":"8","author":"Koch","year":"2017","journal-title":"Front. Plant Sci"},{"key":"2020011802263117100_ref14","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1038\/ng.142","article-title":"SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation","volume":"40","author":"Blewitt","year":"2008","journal-title":"Nature Genet"},{"key":"2020011802263117100_ref15","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":"2020011802263117100_ref16","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.nmd.2011.09.004","article-title":"Best practice guidelines on genetic diagnostics of Facioscapulohumeral muscular dystrophy: workshop 9th June 2010, LUMC, Leiden, the Netherlands","volume":"22","author":"Lemmers","year":"2012","journal-title":"Neuromuscul. Disord"},{"key":"2020011802263117100_ref17","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1038\/ejhg.2014.191","article-title":"Diagnostic approach for FSHD revisited: SMCHD1 mutations cause FSHD2 and act as modifiers of disease severity in FSHD1","volume":"23","author":"Larsen","year":"2015","journal-title":"Eur. J. Hum. Genet"},{"key":"2020011802263117100_ref18","first-page":"1229","article-title":"Facioscapulohumeral muscular dystrophy. Compr","volume":"7","author":"De Simone","year":"2017","journal-title":"Physiol."},{"key":"2020011802263117100_ref19","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1002\/ana.24640","article-title":"Magnetic resonance imaging in a large cohort of facioscapulohumeral muscular dystrophy patients: pattern refinement and implications for clinical trials","volume":"79","author":"Tasca","year":"2016","journal-title":"Ann. Neurol."},{"key":"2020011802263117100_ref20","doi-asserted-by":"crossref","first-page":"e100292","DOI":"10.1371\/journal.pone.0100292","article-title":"Upper girdle imaging in facioscapulohumeral muscular dystrophy","volume":"9","author":"Tasca","year":"2014","journal-title":"PLoS One"},{"key":"2020011802263117100_ref21","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.3389\/fneur.2018.01027","article-title":"Digenic inheritance of shortened repeat units of the D4Z4 region and a loss-of-function variant in SMCHD1 in a family with FSHD","volume":"9","author":"Cascella","year":"2018","journal-title":"Front. Neurol."},{"key":"2020011802263117100_ref22","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/ng.3776","article-title":"Many faces of SMCHD1","volume":"49","author":"Wilkie","year":"2017","journal-title":"Nat. Genet."},{"key":"2020011802263117100_ref23","doi-asserted-by":"crossref","DOI":"10.1136\/jmedgenet-2019-106168","article-title":"SMCHD1 mutation spectrum for facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS) reveals disease-specific localisation of variants in the ATPase domain","author":"Lemmers","year":"2019","journal-title":"J. Med. Genet"},{"key":"2020011802263117100_ref24","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":"2020011802263117100_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":"van den Boogaard","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"2020011802263117100_ref26","doi-asserted-by":"crossref","first-page":"e108411","DOI":"10.1371\/journal.pone.0108411","article-title":"Next-generation sequencing analysis of miRNA expression in control and FSHD myogenesis","volume":"9","author":"Colangelo","year":"2014","journal-title":"PLoS One"},{"key":"2020011802263117100_ref27","doi-asserted-by":"crossref","first-page":"701","DOI":"10.3389\/fneur.2018.00701","article-title":"Application of precision medicine in neurodegenerative diseases","volume":"9","author":"Strafella","year":"2018","journal-title":"Front. Neurol."},{"key":"2020011802263117100_ref28","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1038\/eye.2017.192","article-title":"Assessing individual risk for AMD with genetic counseling, family history, and genetic testing","volume":"32","author":"Cascella","year":"2017","journal-title":"Eye (Lond)"},{"key":"2020011802263117100_ref29","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":"2020011802263117100_ref30","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1007\/s00415-016-8123-2","article-title":"A novel clinical tool to classify facioscapulohumeral muscular dystrophy phenotypes","volume":"263","author":"Ricci","year":"2016","journal-title":"J. Neurol."},{"key":"2020011802263117100_ref31","doi-asserted-by":"crossref","first-page":"D506","DOI":"10.1093\/nar\/gky1049","article-title":"UniProt: a worldwide hub of protein knowledge","volume":"8","author":"UniProt Consortium","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"2020011802263117100_ref32","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: mutation prediction for the deep-sequencing age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat Methods"},{"key":"2020011802263117100_ref33","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1093\/bioinformatics\/bty897","article-title":"VarSome: the human genomic variant search engine","volume":"35","author":"Kopanos","year":"2018","journal-title":"Bioinformatics."},{"key":"2020011802263117100_ref34","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/nprot.2015.053","article-title":"The Phyre2 web portal for protein modeling, prediction and analysis","volume":"10","author":"Kelley","year":"2015","journal-title":"Nat. Protoc."},{"key":"2020011802263117100_ref35","doi-asserted-by":"crossref","first-page":"D257","DOI":"10.1093\/nar\/gku949","article-title":"SMART: recent updates, new developments and status in 2015","volume":"43","author":"Letunic","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"2020011802263117100_ref36","doi-asserted-by":"crossref","first-page":"D493","DOI":"10.1093\/nar\/gkx922","article-title":"20 years of the SMART protein domain annotation resource","volume":"46","author":"Letunic","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2020011802263117100_ref37"},{"key":"2020011802263117100_ref38","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1016\/j.jmb.2019.04.009","article-title":"Can predicted protein 3D structures provide reliable insights into whether missense variants are disease associated","volume":"431","author":"Ittisoponpisan","year":"2019","journal-title":"J. Mol. Biol."},{"key":"2020011802263117100_ref39","doi-asserted-by":"crossref","first-page":"e67","DOI":"10.1093\/nar\/gkp215","article-title":"Human splicing finder: an online bioinformatics tool to predict splicing signals","volume":"37","author":"Desmet","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"2020011802263117100_ref40","doi-asserted-by":"crossref","first-page":"D86","DOI":"10.1093\/nar\/gkt1028","article-title":"PolymiRTS Database 3.0: linking polymorphisms in microRNAs and their target sites with human diseases and biological pathways","volume":"42","author":"Bhattacharya","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"2020011802263117100_ref41","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddz239\/31269467\/ddz239.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/28\/23\/3912\/31874834\/ddz239.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/28\/23\/3912\/31874834\/ddz239.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,1,18]],"date-time":"2020-01-18T02:26:47Z","timestamp":1579314407000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/28\/23\/3912\/5584953"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,10]]},"references-count":41,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2019,10,10]]},"published-print":{"date-parts":[[2019,12,1]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddz239","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,12,1]]},"published":{"date-parts":[[2019,10,10]]}}}