{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T17:07:49Z","timestamp":1789664869225,"version":"4.0.1"},"reference-count":11,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Moebius syndrome (OMIM #157900) is a rare congenital cranial dysinnervation disorder characterized by abducens (CN VI) and facial (CN VII) nerve palsies with variable craniofacial and limb anomalies. Despite advances in genomic testing, the majority of patients remain genetically unexplained. Episignature testing, which detects syndrome\u2010specific DNA methylation patterns, has emerged as a complementary diagnostic tool for conditions with shared developmental mechanisms. We describe an 8\u2010month\u2010old male born prematurely with bilateral clubfoot, craniofacial dysmorphism, feeding difficulty requiring gastrostomy tube placement, and respiratory failure requiring tracheostomy. Neuroimaging demonstrated absence of bilateral abducens and facial nerves with pontocerebellar hypoplasia, supporting a clinical diagnosis of Moebius syndrome. Extensive genetic evaluation, including genome sequencing and targeted testing for hypotonia and hypoventilation syndromes, was nondiagnostic. Episignature analysis revealed a moderately positive methylation signature consistent with a recurrent constellation of embryonic malformation (RCEM), concordant with two of three previously validated RCEM classifier models. To our knowledge, this is the first report of a patient with a positive RCEM episignature and Moebius syndrome, suggesting a common embryologic pathway. Episignature testing may represent a valuable diagnostic tool in patients with Moebius syndrome and related craniofacial\u2013limb malformation spectra when conventional genomic testing is unrevealing.<\/jats:p>","DOI":"10.1002\/ajmg.a.70300","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T16:14:07Z","timestamp":1789661647000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Moebius\u2010Plus Phenotype With Positive\n                    <scp>RCEM<\/scp>\n                    Episignature May Indicate Broader Embryologic Malformation Spectrum Detectable by Methylation Profiling"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2620-5392","authenticated-orcid":false,"given":"Hannah","family":"Peck","sequence":"first","affiliation":[{"name":"Department of Pediatrics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8140-336X","authenticated-orcid":false,"given":"Laura A.","family":"Krueger","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Human Genetics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1233-4502","authenticated-orcid":false,"given":"Ethan D.","family":"Sperry","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Human Genetics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Monsberger","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Human Genetics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaindy","family":"Grunwald","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Human Genetics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7305-0442","authenticated-orcid":false,"given":"Daniel T.","family":"Swarr","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0770-5516","authenticated-orcid":false,"given":"Robert J.","family":"Hopkin","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7447-8117","authenticated-orcid":false,"given":"Amelle","family":"Shillington","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio 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