{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T23:02:45Z","timestamp":1781650965944,"version":"3.54.5"},"reference-count":31,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T00:00:00Z","timestamp":1701043200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82200599"],"award-info":[{"award-number":["82200599"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The Erb\u2010B2 receptor tyrosine kinase 3 (<jats:italic>ERBB3<\/jats:italic>) gene was first identified as a cause of lethal congenital contracture syndrome (OMIM 607598), while a recent study reported six additional patients carrying <jats:italic>ERBB3<\/jats:italic> variants which exhibited distinct clinical features with evident intestinal dysmotility (OMIM <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/omim.org\/entry\/243180\">243180<\/jats:ext-link>). The potential connection between these phenotypes remains unknown, and the <jats:italic>ERBB3<\/jats:italic>\u2010related phenotype spectrum needs to be better characterized. Here, we described a patient presenting with a multisystemic syndrome including skip segment Hirschsprung disease, bilateral clubfoot deformity, and cardiac defect. Trio\u2010whole exome sequencing revealed a novel compound heterozygous variant (c.1914\u20107C&gt;G; c.2942_2945del) in the patient's <jats:italic>ERBB3<\/jats:italic> gene. RT\u2010PCR and in vitro minigene analysis demonstrated that variant c.1914\u20107C&gt;G caused aberrant mRNA splicing. Both variants resulted in premature termination codon and complete loss of <jats:italic>ERBB3<\/jats:italic> function. <jats:italic>erbb3b<\/jats:italic> knockdown in zebrafish simultaneously caused a reduction in enteric neurons in the distal intestine, craniofacial cartilage defects, and micrognathia, which phenotypically mimics <jats:italic>ERBB3<\/jats:italic>\u2010related intestinal dysmotility and some features of lethal congenital contracture syndrome in human patients. These findings provide further patient and animal evidence supporting that <jats:italic>ERBB3<\/jats:italic> deficiency causes a complex syndrome involving multiple systems with phenotypic variability among distinct individuals.<\/jats:p>","DOI":"10.1111\/cge.14462","type":"journal-article","created":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T00:11:09Z","timestamp":1701130269000},"page":"283-293","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<i>ERBB3<\/i> deficiency causes a multisystemic syndrome in human patient and zebrafish"],"prefix":"10.1111","volume":"105","author":[{"given":"Keqiang","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pediatric Surgery, Xinhua Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition  Shanghai China"},{"name":"Shanghai Institute for Pediatric Research  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ru","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Xinhua Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minzhong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Xinhua Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Xinhua Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Xinhua Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Xinhua Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition  Shanghai China"},{"name":"Shanghai Institute for Pediatric Research  Shanghai 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