{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T03:39:34Z","timestamp":1792640374714,"version":"4.5.0"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T00:00:00Z","timestamp":1692662400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> Despite the progress made in the study of Facioscapulohumeral Dystrophy (FSHD), the wide heterogeneity of disease complicates its diagnosis and the genotype-phenotype correlation among patients and within families. In this context, the present work employed Whole Exome Sequencing (WES) to investigate known and unknown genetic contributors that may be involved in FSHD and may represent potential disease modifiers, even in presence of a <jats:italic>D4Z4<\/jats:italic> Reduced Allele (DRA).<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> A cohort of 126 patients with clinical signs of FSHD were included in the study, which were characterized by <jats:italic>D4Z4<\/jats:italic> sizing, methylation analysis and WES. Specific protocols were employed for <jats:italic>D4Z4<\/jats:italic> sizing and methylation analysis, whereas the Illumina<jats:sup>\u00ae<\/jats:sup> Next-Seq 550 system was utilized for WES. The study included both patients with a DRA compatible with FSHD diagnosis and patients with longer <jats:italic>D4Z4<\/jats:italic> alleles. In case of patients harboring relevant variants from WES, the molecular analysis was extended to the family members.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> The WES data analysis highlighted 20 relevant variants, among which 14 were located in known genetic modifiers (<jats:italic>SMCHD1<\/jats:italic>, <jats:italic>DNMT3B<\/jats:italic> and <jats:italic>LRIF1<\/jats:italic>) and 6 in candidate genes (<jats:italic>CTCF<\/jats:italic>, <jats:italic>DNMT1<\/jats:italic>, <jats:italic>DNMT3A<\/jats:italic>, <jats:italic>EZH2<\/jats:italic> and <jats:italic>SUV39H1<\/jats:italic>). Most of them were found together with a permissive short (4\u20137\u00a0RU) or borderline\/long DRA (8\u201320\u00a0RU), supporting the possibility that different genes can contribute to disease heterogeneity in presence of a FSHD permissive background. The segregation and methylation analysis among family members, together with clinical findings, provided a more comprehensive picture of patients.<\/jats:p><jats:p><jats:bold>Discussion:<\/jats:bold> Our results support FSHD pathomechanism being complex with a multigenic contribution by several known (<jats:italic>SMCHD1<\/jats:italic>, <jats:italic>DNMT3B<\/jats:italic>, <jats:italic>LRIF1<\/jats:italic>) and possibly other candidate genes (<jats:italic>CTCF<\/jats:italic>, <jats:italic>DNMT1<\/jats:italic>, <jats:italic>DNMT3A<\/jats:italic>, <jats:italic>EZH2<\/jats:italic>, <jats:italic>SUV39H1<\/jats:italic>) to disease penetrance and expressivity. Our results further emphasize the importance of extending the analysis of molecular findings within the proband\u2019s family, with the purpose of providing a broader framework for understanding single cases and allowing finer genotype-phenotype correlations in FSHD-affected families.<\/jats:p>","DOI":"10.3389\/fgene.2023.1235589","type":"journal-article","created":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T10:15:01Z","timestamp":1692699301000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Whole exome sequencing highlights rare variants in CTCF, DNMT1, DNMT3A, EZH2 and SUV39H1 as associated with FSHD"],"prefix":"10.3389","volume":"14","author":[{"given":"Claudia","family":"Strafella","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerio","family":"Caputo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Bortolani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Torchia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenica","family":"Megalizzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Trastulli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Monforte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Colantoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Caltagirone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enzo","family":"Ricci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Tasca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Cascella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emiliano","family":"Giardina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,22]]},"reference":[{"key":"B1","article-title":"A circulating biomarker of facioscapulohumeral muscular dystrophy clinical severity, valid in skeletal muscle and blood","author":"Banerji","year":"2022","journal-title":"bioRxiv"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2224","DOI":"10.1093\/hmg\/ddz043","article-title":"PAX7 target gene repression is a superior FSHD biomarker than DUX4 target gene activation, associating with pathological severity and identifying FSHD at the single-cell level","volume":"28","author":"Banerji","year":"2019","journal-title":"Hum. 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