{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T14:07:13Z","timestamp":1790518033140,"version":"4.1.0"},"reference-count":74,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T00:00:00Z","timestamp":1663113600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Genetic diagnosis of facioscapulohumeral muscular dystrophy (FSHD) remains a challenge in clinical practice as it cannot be detected by standard sequencing methods despite being the third most common muscular dystrophy. The conventional diagnostic strategy addresses the known genetic parameters of FSHD: the required presence of a permissive haplotype, a size reduction of the D4Z4 repeat of chromosome 4q35 (defining FSHD1) or a pathogenic variant in an epigenetic suppressor gene (consistent with FSHD2). Incomplete penetrance and epistatic effects of the underlying genetic parameters as well as epigenetic parameters (D4Z4 methylation) pose challenges to diagnostic accuracy and hinder prediction of clinical severity.<\/jats:p>\n                  <jats:p>In order to circumvent the known limitations of conventional diagnostics and to complement genetic parameters with epigenetic ones, we developed and validated a multistage diagnostic workflow that consists of a haplotype analysis and a high-throughput methylation profile analysis (FSHD-MPA). FSHD-MPA determines the average global methylation level of the D4Z4 repeat array as well as the regional methylation of the most distal repeat unit by combining bisulphite conversion with next-generation sequencing and a bioinformatics pipeline and uses these as diagnostic parameters. We applied the diagnostic workflow to a cohort of 148 patients and compared the epigenetic parameters based on FSHD-MPA to genetic parameters of conventional genetic testing. In addition, we studied the correlation of repeat length and methylation level within the most distal repeat unit with age-corrected clinical severity and age at disease onset in FSHD patients. The results of our study show that FSHD-MPA is a powerful tool to accurately determine the epigenetic parameters of FSHD, allowing discrimination between FSHD patients and healthy individuals, while simultaneously distinguishing FSHD1 and FSHD2. The strong correlation between methylation level and clinical severity indicates that the methylation level determined by FSHD-MPA accounts for differences in disease severity among individuals with similar genetic parameters. Thus, our findings further confirm that epigenetic parameters rather than genetic parameters represent FSHD disease status and may serve as a valuable biomarker for disease status.<\/jats:p>","DOI":"10.1093\/brain\/awac336","type":"journal-article","created":{"date-parts":[[2022,9,12]],"date-time":"2022-09-12T16:29:07Z","timestamp":1663000147000},"page":"1388-1402","source":"Crossref","is-referenced-by-count":36,"title":["Methylation of the 4q35 D4Z4 repeat defines disease status in facioscapulohumeral muscular dystrophy"],"prefix":"10.1093","volume":"146","author":[{"given":"Hannes","family":"Erdmann","sequence":"first","affiliation":[{"name":"Medical Genetics Center (MGZ) , 80335 Munich , Germany"},{"name":"Friedrich-Baur-Institute, Department of Neurology, Klinikum der Universit\u00e4t, Ludwig-Maximilians-Universit\u00e4t , 80336 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florentine","family":"Scharf","sequence":"additional","affiliation":[{"name":"Medical Genetics Center (MGZ) , 80335 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Gehling","sequence":"additional","affiliation":[{"name":"Medical Genetics Center (MGZ) , 80335 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Benet-Pag\u00e8s","sequence":"additional","affiliation":[{"name":"Medical Genetics Center (MGZ) , 80335 Munich , Germany"},{"name":"Institute of Neurogenomics, Helmholtz Center Munich , 85764 Neuherberg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sibylle","family":"Jakubiczka","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Universit\u00e4tsklinikum Magdeburg, Otto-von-Guericke Universit\u00e4t , 39120 Magdeburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Becker","sequence":"additional","affiliation":[{"name":"Medical Genetics Center (MGZ) , 80335 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Seipelt","sequence":"additional","affiliation":[{"name":"Department of Neurology, Universit\u00e4tsklinikum Marburg, Philipps-University Marburg , 35043 Marburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Kleefeld","sequence":"additional","affiliation":[{"name":"Department of Neurology and Experimental Neurology, Charit\u00e9 Berlin , 10117 Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl Christian","family":"Knop","sequence":"additional","affiliation":[{"name":"Neurologische Praxis Neuer Wall , 20354 Hamburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva-Christina","family":"Prott","sequence":"additional","affiliation":[{"name":"Praxis f\u00fcr Humangenetik , 42103 Wuppertal , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Hiebeler","sequence":"additional","affiliation":[{"name":"Friedrich-Baur-Institute, Department of Neurology, Klinikum der Universit\u00e4t, Ludwig-Maximilians-Universit\u00e4t , 80336 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7291-5408","authenticated-orcid":false,"given":"Federica","family":"Montagnese","sequence":"additional","affiliation":[{"name":"Friedrich-Baur-Institute, Department of Neurology, Klinikum der Universit\u00e4t, Ludwig-Maximilians-Universit\u00e4t , 80336 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dieter","family":"Gl\u00e4ser","sequence":"additional","affiliation":[{"name":"Genetikum , 89231 Neu-Ulm , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Vorgerd","sequence":"additional","affiliation":[{"name":"Department of Neurology, Berufgenossenschaftliches Universit\u00e4tsklinikum Bergmannsheil, Ruhr-Universit\u00e4t Bochum , 44789 Bochum , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Hagenacker","sequence":"additional","affiliation":[{"name":"Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen , 45147 Essen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maggie C","family":"Walter","sequence":"additional","affiliation":[{"name":"Friedrich-Baur-Institute, Department of Neurology, Klinikum der Universit\u00e4t, Ludwig-Maximilians-Universit\u00e4t , 80336 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Reilich","sequence":"additional","affiliation":[{"name":"Friedrich-Baur-Institute, Department of Neurology, Klinikum der Universit\u00e4t, Ludwig-Maximilians-Universit\u00e4t , 80336 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Neuhann","sequence":"additional","affiliation":[{"name":"Medical Genetics Center (MGZ) , 80335 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Zenker","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Universit\u00e4tsklinikum Magdeburg, Otto-von-Guericke Universit\u00e4t , 39120 Magdeburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elke","family":"Holinski-Feder","sequence":"additional","affiliation":[{"name":"Medical Genetics Center (MGZ) , 80335 Munich , Germany"},{"name":"Department of Medicine IV, Klinikum der Universit\u00e4t, Ludwig-Maximilians-Universit\u00e4t , 80336 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Schoser","sequence":"additional","affiliation":[{"name":"Friedrich-Baur-Institute, Department of Neurology, Klinikum der Universit\u00e4t, Ludwig-Maximilians-Universit\u00e4t , 80336 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2757-8131","authenticated-orcid":false,"given":"Angela","family":"Abicht","sequence":"additional","affiliation":[{"name":"Medical Genetics Center (MGZ) , 80335 Munich , Germany"},{"name":"Friedrich-Baur-Institute, Department of Neurology, Klinikum der Universit\u00e4t, Ludwig-Maximilians-Universit\u00e4t , 80336 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,9,14]]},"reference":[{"key":"2023041916393347300_awac336-B1","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":"2023041916393347300_awac336-B2","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":"2023041916393347300_awac336-B3","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1136\/practneurol-2015-001353","article-title":"What\u2019s in a name? The clinical features of facioscapulohumeral muscular dystrophy","volume":"16","author":"Mul","year":"2016","journal-title":"Pract Neurol"},{"key":"2023041916393347300_awac336-B4","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":"2023041916393347300_awac336-B5","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1002\/mus.21722","article-title":"Facioscapulohumeral muscular dystrophy presenting with isolated axial myopathy and bent spine syndrome","volume":"42","author":"Kottlors","year":"2010","journal-title":"Muscle Nerve"},{"key":"2023041916393347300_awac336-B6","doi-asserted-by":"crossref","first-page":"21648","DOI":"10.1038\/s41598-020-78578-7","article-title":"Large genotype\u2013phenotype study in carriers of D4Z4 borderline alleles provides guidance for facioscapulohumeral muscular dystrophy diagnosis","volume":"10","author":"Ricci","year":"2020","journal-title":"Sci Rep"},{"key":"2023041916393347300_awac336-B7","doi-asserted-by":"crossref","first-page":"3408","DOI":"10.1093\/brain\/awt226","article-title":"Large scale genotype\u2013phenotype analyses indicate that novel prognostic tools are required for families with facioscapulohumeral muscular dystrophy","volume":"136","author":"Ricci","year":"2013","journal-title":"Brain"},{"key":"2023041916393347300_awac336-B8","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1016\/j.nmd.2017.09.007","article-title":"Early onset facioscapulohumeral dystrophy\u2014A systematic review using individual patient data","volume":"27","author":"Goselink","year":"2017","journal-title":"Neuromuscul Disord"},{"key":"2023041916393347300_awac336-B9","first-page":"99","article-title":"High proportion of new mutations and possible anticipation in Brazilian facioscapulohumeral muscular dystrophy families","volume":"56","author":"Zatz","year":"1995","journal-title":"Am J Hum Genet"},{"key":"2023041916393347300_awac336-B10","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1212\/WNL.43.2.345","article-title":"Extreme variability of expression in monozygotic twins with FSH muscular dystrophy","volume":"43","author":"Tawil","year":"1993","journal-title":"Neurology"},{"key":"2023041916393347300_awac336-B11","doi-asserted-by":"crossref","first-page":"e204040","DOI":"10.1001\/jamanetworkopen.2020.4040","article-title":"Phenotypic variability among patients with D4Z4 reduced allele facioscapulohumeral muscular dystrophy","volume":"3","author":"Ruggiero","year":"2020","journal-title":"JAMA Netw"},{"key":"2023041916393347300_awac336-B12","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":"2023041916393347300_awac336-B13","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1136\/jmg.28.10.655","article-title":"Genetic counselling in facioscapulohumeral muscular dystrophy","volume":"28","author":"Lunt","year":"1991","journal-title":"J Med Genet"},{"key":"2023041916393347300_awac336-B14","doi-asserted-by":"crossref","first-page":"93","DOI":"10.3390\/genes8030093","article-title":"Antisense oligonucleotides used to target the DUX4 mRNA as therapeutic approaches in FacioScapuloHumeral muscular dystrophy (FSHD)","volume":"8","author":"Ansseau","year":"2017","journal-title":"Genes (Basel)"},{"key":"2023041916393347300_awac336-B15","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1016\/j.ymthe.2020.10.010","article-title":"DUX4 Transcript knockdown with antisense 2\u2032-O-methoxyethyl gapmers for the treatment of facioscapulohumeral muscular dystrophy","volume":"29","author":"Lim","year":"2021","journal-title":"Mol Ther"},{"key":"2023041916393347300_awac336-B16","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1093\/hmg\/ddw015","article-title":"Antisense targeting of 3\u2032 end elements involved in DUX4 mRNA processing is an efficient therapeutic strategy for facioscapulohumeral dystrophy: A new gene-silencing approach","volume":"25","author":"Marsollier","year":"2016","journal-title":"Hum Mol Genet"},{"key":"2023041916393347300_awac336-B17","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.omtn.2020.12.004","article-title":"Designed U7 snRNAs inhibit DUX4 expression and improve FSHD-associated outcomes in DUX4 overexpressing cells and FSHD patient myotubes","volume":"23","author":"Rashnonejad","year":"2020","journal-title":"Mol Ther Nucleic Acids"},{"key":"2023041916393347300_awac336-B18","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1212\/01.wnl.0000240071.62540.6f","article-title":"Diagnostic challenges in facioscapulohumeral muscular dystrophy","volume":"67","author":"Sacconi","year":"2006","journal-title":"Neurology"},{"key":"2023041916393347300_awac336-B19","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.2174\/1566524014666141010155054","article-title":"Facioscapulohumeral muscular dystrophy: More complex than it appears","volume":"14","author":"Ricci","year":"2014","journal-title":"Curr Mol Med"},{"key":"2023041916393347300_awac336-B20","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":"2023041916393347300_awac336-B21","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":"2023041916393347300_awac336-B22","doi-asserted-by":"crossref","first-page":"e444","DOI":"10.1212\/WNL.0000000000005915","article-title":"A family-based study into penetrance in facioscapulohumeral muscular dystrophy type 1","volume":"91","author":"Wohlgemuth","year":"2018","journal-title":"Neurology"},{"key":"2023041916393347300_awac336-B23","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 Richard","year":"2010","journal-title":"Science"},{"key":"2023041916393347300_awac336-B24","doi-asserted-by":"crossref","first-page":"2414","DOI":"10.1093\/hmg\/ddp180","article-title":"RNA Transcripts, miRNA-sized fragments and proteins produced from D4Z4 units: New candidates for the pathophysiology of facioscapulohumeral dystrophy","volume":"18","author":"Snider","year":"2009","journal-title":"Hum Mol Genet"},{"key":"2023041916393347300_awac336-B25","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1111\/cge.13726","article-title":"Consequences of epigenetic derepression in facioscapulohumeral muscular dystrophy","volume":"97","author":"Greco","year":"2020","journal-title":"Clin Genet"},{"key":"2023041916393347300_awac336-B26","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1038\/s41467-017-00730-1","article-title":"Muscle pathology from stochastic low level DUX4 expression in an FSHD mouse model","volume":"8","author":"Bosnakovski","year":"2017","journal-title":"Nat Commun"},{"key":"2023041916393347300_awac336-B27","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.devcel.2011.11.013","article-title":"DUX4 Activates germline genes, retroelements, and immune mediators: Implications for facioscapulohumeral dystrophy","volume":"22","author":"Geng","year":"2012","journal-title":"Dev Cell"},{"key":"2023041916393347300_awac336-B28","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1086\/521986","article-title":"Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy","volume":"81","author":"Lemmers","year":"2007","journal-title":"Am J Hum Genet"},{"key":"2023041916393347300_awac336-B29","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/ng0992-26","article-title":"Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy","volume":"2","author":"Wijmenga","year":"1992","journal-title":"Nat Genet"},{"key":"2023041916393347300_awac336-B30","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1093\/hmg\/2.12.2037","article-title":"FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit","volume":"2","author":"Deutekom","year":"1993","journal-title":"Hum Mol Genet"},{"key":"2023041916393347300_awac336-B31","volume-title":"Facioscapulohumeral Muscular Dystrophy. GeneReviews\u00ae [Internet]","author":"Preston","year":"1993\u20132022"},{"key":"2023041916393347300_awac336-B32","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":"2023041916393347300_awac336-B33","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":"2023041916393347300_awac336-B34","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":"2023041916393347300_awac336-B35","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1002\/ana.10057","article-title":"Complete allele information in the diagnosis of facioscapulohumeral muscular dystrophy by triple DNA analysis","volume":"50","author":"Lemmers","year":"2001","journal-title":"Ann Neurol"},{"key":"2023041916393347300_awac336-B36","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1016\/j.nmd.2021.09.010","article-title":"Facioscapulohumeral muscular dystrophy type 2: An update on the clinical, genetic, and molecular findings","volume":"31","author":"Jia","year":"2021","journal-title":"Neuromuscul Disord"},{"key":"2023041916393347300_awac336-B37","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1002\/humu.21091","article-title":"Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD","volume":"30","author":"de Greef","year":"2009","journal-title":"Hum Mutat"},{"key":"2023041916393347300_awac336-B38","doi-asserted-by":"crossref","first-page":"3488","DOI":"10.1093\/hmg\/ddy236","article-title":"Cis D4Z4 repeat duplications associated with facioscapulohumeral muscular dystrophy type 2","volume":"27","author":"Lemmers","year":"2018","journal-title":"Hum Mol Genet"},{"key":"2023041916393347300_awac336-B39","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":"2023041916393347300_awac336-B40","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1002\/ana.22513","article-title":"Molecular combing reveals allelic combinations in facioscapulohumeral dystrophy","volume":"70","author":"Nguyen","year":"2011","journal-title":"Ann Neurol"},{"key":"2023041916393347300_awac336-B41","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1002\/humu.23304","article-title":"Molecular combing reveals complex 4q35 rearrangements in facioscapulohumeral dystrophy","volume":"38","author":"Nguyen","year":"2017","journal-title":"Hum Mutat"},{"key":"2023041916393347300_awac336-B42","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1016\/j.jmoldx.2021.07.021","article-title":"Validation of optical genome mapping for the molecular diagnosis of facioscapulohumeral muscular dystrophy","volume":"23","author":"Stence","year":"2021","journal-title":"J Mol Diagn"},{"key":"2023041916393347300_awac336-B43","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":"2023041916393347300_awac336-B44","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"},{"key":"2023041916393347300_awac336-B45","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/1868-7083-6-23","article-title":"Identifying diagnostic DNA methylation profiles for facioscapulohumeral muscular dystrophy in blood and saliva using bisulfite sequencing","volume":"6","author":"Jones","year":"2014","journal-title":"Clin Epigenetics"},{"key":"2023041916393347300_awac336-B46","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1093\/hmg\/3.8.1287","article-title":"Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy","volume":"3","author":"Hewitt","year":"1994","journal-title":"Hum Mol Genet"},{"key":"2023041916393347300_awac336-B47","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/ng1262","article-title":"Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy","volume":"35","author":"van Overveld","year":"2003","journal-title":"Nat Genet"},{"key":"2023041916393347300_awac336-B48","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.3390\/diagnostics11081469","article-title":"Precise epigenetic analysis using targeted bisulfite genomic sequencing distinguishes FSHD1, FSHD2, and healthy subjects","volume":"11","author":"Gould","year":"2021","journal-title":"Diagnostics"},{"key":"2023041916393347300_awac336-B49","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1093\/hmg\/4.5.951","article-title":"Correlation between fragment size at D4F104S1 and age at onset or at wheelchair use, with a possible generational effect, accounts for much phenotypic variation in 4q35-facioscapulohumeral muscular dystrophy (FSHD)","volume":"4","author":"Lunt","year":"1995","journal-title":"Hum Mol Genet"},{"key":"2023041916393347300_awac336-B50","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1002\/ana.410390610","article-title":"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":"2023041916393347300_awac336-B51","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1111\/cge.13446","article-title":"Phenotype\u2013genotype relations in facioscapulohumeral muscular dystrophy type 1","volume":"94","author":"Mul","year":"2018","journal-title":"Clin Genet"},{"key":"2023041916393347300_awac336-B52","doi-asserted-by":"crossref","first-page":"3451","DOI":"10.1093\/brain\/awab326","article-title":"Predictors of functional outcomes in patients with facioscapulohumeral muscular dystrophy","volume":"144","author":"Katz","year":"2021","journal-title":"Brain"},{"key":"2023041916393347300_awac336-B53","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s13148-015-0072-6","article-title":"Individual epigenetic status of the pathogenic D4Z4 macrosatellite correlates with disease in facioscapulohumeral muscular dystrophy","volume":"7","author":"Jones","year":"2015","journal-title":"Clin Epigenetics"},{"key":"2023041916393347300_awac336-B54","doi-asserted-by":"crossref","first-page":"642858","DOI":"10.3389\/fphar.2021.642858","article-title":"Genetic approaches for the treatment of facioscapulohumeral muscular dystrophy","volume":"12","author":"Lim","year":"2021","journal-title":"Front Pharmacol"},{"key":"2023041916393347300_awac336-B55","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":"Van Overveld","year":"2005","journal-title":"Ann Neurol"},{"key":"2023041916393347300_awac336-B56","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1136\/jmg.2009.076703","article-title":"FSH dystrophy and a subtelomeric 4q haplotype: A new assay and associations with disease","volume":"47","author":"Tsumagari","year":"2010","journal-title":"J Med Genet"},{"key":"2023041916393347300_awac336-B57","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"},{"key":"2023041916393347300_awac336-B58","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1038\/gim.2017.37","article-title":"Sherloc: A comprehensive refinement of the ACMG\u2013AMP variant classification criteria","volume":"19","author":"Nykamp","year":"2017","journal-title":"Genet Med"},{"key":"2023041916393347300_awac336-B59","doi-asserted-by":"crossref","first-page":"18157","DOI":"10.1073\/pnas.0708659104","article-title":"DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1","volume":"104","author":"Dixit","year":"2007","journal-title":"Proc Natl Acad Sci"},{"key":"2023041916393347300_awac336-B60","doi-asserted-by":"crossref","first-page":"4419","DOI":"10.1093\/hmg\/dds284","article-title":"Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis","volume":"21","author":"Jones","year":"2012","journal-title":"Hum Mol Genet"},{"key":"2023041916393347300_awac336-B61","doi-asserted-by":"crossref","first-page":"e1001181","DOI":"10.1371\/journal.pgen.1001181","article-title":"Facioscapulohumeral dystrophy: Incomplete suppression of a retrotransposed gene","volume":"6","author":"Snider","year":"2010","journal-title":"PLOS Genet"},{"key":"2023041916393347300_awac336-B62","doi-asserted-by":"crossref","first-page":"17547","DOI":"10.1038\/s41598-020-74687-5","article-title":"Evaluation of blood gene expression levels in facioscapulohumeral muscular dystrophy patients","volume":"10","author":"Signorelli","year":"2020","journal-title":"Sci Rep"},{"key":"2023041916393347300_awac336-B63","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.ajhg.2010.01.035","article-title":"Worldwide population analysis of the 4q and 10q subtelomeres identifies only four discrete interchromosomal sequence transfers in human evolution","volume":"86","author":"Lemmers","year":"2010","journal-title":"Am J Hum Genet"},{"key":"2023041916393347300_awac336-B64","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1093\/hmg\/5.12.1997","article-title":"Evidence for subtelomeric exchange of 3.3 kb tandemly repeated units between chromosomes 4q35 and 10q26: implications for genetic counselling and etiology of FSHD1","volume":"5","author":"van Deutekom","year":"1996","journal-title":"Hum Mol Genet"},{"key":"2023041916393347300_awac336-B65","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":"2023041916393347300_awac336-B66","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":"2023041916393347300_awac336-B67","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":"2023041916393347300_awac336-B68","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1086\/302730","article-title":"De novo facioscapulohumeral muscular dystrophy: Frequent somatic mosaicism, sex-dependent phenotype, and the role of mitotic transchromosomal repeat interaction between chromosomes 4 and 10","volume":"66","author":"van der Maarel","year":"2000","journal-title":"Am J Hum Genet"},{"key":"2023041916393347300_awac336-B69","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1002\/ana.20106","article-title":"Somatic mosaicism in FSHD often goes undetected","volume":"55","author":"Lemmers","year":"2004","journal-title":"Ann Neurol"},{"key":"2023041916393347300_awac336-B70","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1136\/jmedgenet-2015-103436","article-title":"Allele-specific DNA hypomethylation characterises FSHD1 and FSHD2","volume":"53","author":"Calandra","year":"2016","journal-title":"J Med Genet"},{"key":"2023041916393347300_awac336-B71","doi-asserted-by":"crossref","first-page":"258","DOI":"10.3390\/genes11030258","article-title":"Does DNA methylation matter in FSHD?","volume":"11","author":"Salsi","year":"2020","journal-title":"Genes (Basel)"},{"key":"2023041916393347300_awac336-B72","doi-asserted-by":"crossref","first-page":"2635","DOI":"10.3390\/ijms21072635","article-title":"Interpretation of the epigenetic signature of facioscapulohumeral muscular dystrophy in light of genotype\u2013phenotype studies","volume":"21","author":"Nikolic","year":"2020","journal-title":"Int J Mol Sci"},{"key":"2023041916393347300_awac336-B73","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1101\/gr.240739.118","article-title":"Long-read single-molecule maps of the functional methylome","volume":"29","author":"Sharim","year":"2019","journal-title":"Genome Res"},{"key":"2023041916393347300_awac336-B74","doi-asserted-by":"crossref","first-page":"14789","DOI":"10.1038\/s41598-017-13712-6","article-title":"Nanopore-based single molecule sequencing of the D4Z4 array responsible for facioscapulohumeral muscular dystrophy","volume":"7","author":"Mitsuhashi","year":"2017","journal-title":"Sci Rep"}],"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awac336\/47887867\/awac336.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/146\/4\/1388\/50031052\/awac336.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/146\/4\/1388\/50031052\/awac336.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,19]],"date-time":"2023-04-19T12:41:51Z","timestamp":1681908111000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/article\/146\/4\/1388\/6696990"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,14]]},"references-count":74,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,9,14]]},"published-print":{"date-parts":[[2023,4,19]]}},"URL":"https:\/\/doi.org\/10.1093\/brain\/awac336","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,4,3]]},"published":{"date-parts":[[2022,9,14]]}}}