{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:09:58Z","timestamp":1791389398596,"version":"4.3.3"},"reference-count":22,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T00:00:00Z","timestamp":1706659200000},"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>Background:<\/jats:bold> Moebius Syndrome (MBS) is a rare congenital neurological disorder characterized by paralysis of facial nerves, impairment of ocular abduction and other variable abnormalities. MBS has been attributed to both environmental and genetic factors as potential causes. Until now only two genes, <jats:italic>PLXND1<\/jats:italic> and <jats:italic>REV3L<\/jats:italic> have been identified to cause MBS.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> We present a 9-year-old male clinically diagnosed with MBS, presenting facial palsy, altered ocular mobility, microglossia, dental anomalies and congenital torticollis. Radiologically, he lacks both abducens nerves and shows altered symmetry of both facial and vestibulocochlear nerves. Whole-exome sequence identified a <jats:italic>de novo<\/jats:italic> missense variant c.643G&amp;gt;A; p.Gly215Arg in <jats:italic>CHN1<\/jats:italic>, encoding the \u03b12-chimaerin protein. The p.Gly215Arg variant is located in the C1 domain of CHN1 where other pathogenic gain of function variants have been reported. Bioinformatic analysis and molecular structural modelling predict a deleterious effect of the missense variant on the protein function.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Our findings support that pathogenic variants in the <jats:italic>CHN1<\/jats:italic> gene may be responsible for different cranial congenital dysinnervation syndromes, including Moebius and Duane retraction syndromes. We propose to include <jats:italic>CHN1<\/jats:italic> in the genetic diagnoses of MBS.<\/jats:p>","DOI":"10.3389\/fgene.2024.1291063","type":"journal-article","created":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T11:12:15Z","timestamp":1706699535000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Case report: Identification of a novel variant p.Gly215Arg in the CHN1 gene causing Moebius syndrome"],"prefix":"10.3389","volume":"15","author":[{"given":"Carmen","family":"Manso-Baz\u00fas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nino","family":"Spataro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Gabau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviana P.","family":"Beltr\u00e1n-Salazar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Pablo","family":"Trujillo-Quintero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuria","family":"Capdevila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Brunet-Vega","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neus","family":"Baena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A Arockia","family":"Jeyaprakash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Martinez-Glez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,1,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1086\/343821","article-title":"Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family","volume":"71","author":"Al-Baradie","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"B2","doi-asserted-by":"publisher","first-page":"104188","DOI":"10.1016\/j.ejmg.2021.104188","article-title":"CHN1 and duane retraction syndrome: expanding the phenotype to cranial nerves development disease","volume":"64","author":"Angelini","year":"2021","journal-title":"Eur. J. Med. Genet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1002\/dneu.22477","article-title":"Axons get ahead: insights into axon guidance and congenital cranial dysinnervation disorders","volume":"77","author":"Chilton","year":"2017","journal-title":"Dev. Neurobiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1136\/archdischild-2014-307035","article-title":"The congenital cranial dysinnervation disorders","volume":"100","author":"Gutowski","year":"2015","journal-title":"Archives Dis. Child."},{"key":"B5","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1186\/s13023-022-02582-5","article-title":"Clinical and genetic characteristics of Chinese patients with congenital cranial dysinnervation disorders","volume":"17","author":"Jia","year":"2022","journal-title":"Orphanet J. Rare Dis."},{"key":"B6","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","article-title":"ClinVar: improving access to variant interpretations and supporting evidence","volume":"46","author":"Landrum","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1126\/science.1156121","article-title":"Human CHN1 mutations hyperactivate alpha2-chimaerin and cause Duane\u2019s retraction syndrome","volume":"321","author":"Miyake","year":"2008","journal-title":"Sci. (New York, N.Y.)"},{"key":"B9","doi-asserted-by":"publisher","first-page":"6321","DOI":"10.1167\/iovs.11-7950","article-title":"Expansion of the CHN1 strabismus phenotype","volume":"52","author":"Miyake","year":"2011","journal-title":"Investigative Ophthalmol. Vis. Sci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1080\/09273970801946737","article-title":"About congenital bilateral abducens and facialis palsy (1888)","volume":"16","author":"M\u00f6bius","year":"2008","journal-title":"Strabismus"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1664","DOI":"10.1172\/JCI88502","article-title":"Mutant \u03b12-chimaerin signals via bidirectional ephrin pathways in Duane retraction syndrome","volume":"127","author":"Nugent","year":"2017","journal-title":"J. Clin. Investigation"},{"key":"B12","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1080\/2576117X.2017.1416242","article-title":"Ophthalmoplegia and congenital cranial dysinnervation disorders","volume":"68","author":"Oystreck","year":"2018","journal-title":"J. Binocul. Vis. Ocular Motil."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.1016\/j.ajhg.2016.03.023","article-title":"Loss of MAFB function in humans and mice causes duane syndrome, aberrant extraocular muscle innervation, and inner-ear defects","volume":"98","author":"Park","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/s13052-016-0256-5","article-title":"Moebius syndrome: clinical features, diagnosis, management and early intervention","volume":"42","author":"Picciolini","year":"2016","journal-title":"Italian J. Pediatr."},{"key":"B15","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.clinimag.2020.10.055","article-title":"Imaging of congenital cranial dysinnervation disorders: what radiologist wants to know?","volume":"71","author":"Razek","year":"2021","journal-title":"Clin. Imaging"},{"key":"B16","doi-asserted-by":"publisher","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. Official J. Am. Coll. Med. Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/1744-9081-9-7","article-title":"A boy with homozygous microdeletion of NEUROG1 presents with a congenital cranial dysinnervation disorder [Moebius syndrome variant]","volume":"9","author":"Schr\u00f6der","year":"2013","journal-title":"Behav. Brain Funct. BBF"},{"key":"B18","doi-asserted-by":"publisher","first-page":"708","DOI":"10.3390\/genes14030708","article-title":"High performance of a dominant\/X-linked gene panel in patients with neurodevelopmental disorders","volume":"14","author":"Spataro","year":"2023","journal-title":"Genes"},{"key":"B19","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/s0094-1298(02)00019-6","article-title":"M\u00f6bius and M\u00f6bius-like patients: etiology, diagnosis, and treatment options","volume":"29","author":"Terzis","year":"2002","journal-title":"Clin. Plastic Surg."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.1038\/ng1636","article-title":"Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development","volume":"37","author":"Tischfield","year":"2005","journal-title":"Nat. Genet."},{"key":"B21","doi-asserted-by":"publisher","first-page":"7199","DOI":"10.1038\/ncomms8199","article-title":"De novo mutations in PLXND1 and REV3L cause M\u00f6bius syndrome","volume":"6","author":"Tomas-Roca","year":"2015","journal-title":"Nat. Commun."},{"key":"B22","first-page":"60","volume-title":"En handbuch der Gesamten augenheilkunde (handbook of opthalmology)","author":"von Graefe","year":"1880"}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2024.1291063\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T11:12:19Z","timestamp":1706699539000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2024.1291063\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,31]]},"references-count":22,"alternative-id":["10.3389\/fgene.2024.1291063"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2024.1291063","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,31]]},"article-number":"1291063"}}