{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:55:44Z","timestamp":1790812544504,"version":"4.1.0"},"reference-count":19,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T00:00:00Z","timestamp":1667174400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["2018M3A9B8021980"],"award-info":[{"award-number":["2018M3A9B8021980"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    ZC4H2 (MIM# 300897) is a nuclear factor involved in various cellular processes including proliferation and differentiation of neural stem cells, ventral spinal patterning and osteogenic and myogenic processes. Pathogenic variants in\n                    <jats:italic>ZC4H2<\/jats:italic>\n                    have been associated with Wieacker\u2010Wolff syndrome (MIM# 314580), an X\u2010linked neurodevelopmental disorder characterized by arthrogryposis, development delay, hypotonia, feeding difficulties, poor growth, skeletal abnormalities, and dysmorphic features. Zebrafish\n                    <jats:italic>zc4h2<\/jats:italic>\n                    null mutants recapitulated the human phenotype, showed complete loss of\n                    <jats:italic>vsx2<\/jats:italic>\n                    expression in brain, and exhibited abnormal swimming and balance problems\n                    <jats:italic>.<\/jats:italic>\n                    Here we report 7 new patients (four males and three females) with\n                    <jats:italic>ZC4H2<\/jats:italic>\n                    \u2010related disorder from six unrelated families. Four of the 6\n                    <jats:italic>ZC4H2<\/jats:italic>\n                    variants are novel: three missense variants, designated as c.142T&gt;A (p.Tyr48Asn), c.558G&gt;A (p.Met186Ile) and c.602C&gt;T (p.Pro201Leu), and a nonsense variant, c.618C&gt;A (p.Cys206*). Two variants were previously reported : a nonsense variant c.199C&gt;T (p.Arg67*) and a splice site variant (c.225+5G&gt;A). Five patients were on the severe spectrum of clinical findings, two of whom had early death. The male patient harboring the p.Met186Ile variant and the female patient that carries the p.Pro201Leu variant have a relatively mild phenotype. Of note, 4\/7 patients had a tethered cord that required a surgical repair. We also demonstrate and discuss previously under\u2010recognized phenotypic features including sleep apnea, arrhythmia, hypoglycemia, and unexpected early death. To study the effect of the missense variants, we performed microinjection of human\n                    <jats:italic>ZC4H2<\/jats:italic>\n                    wild\u2010type or variant mRNAs into\n                    <jats:italic>zc4h2<\/jats:italic>\n                    null mutant zebrafish embryos. The p.Met186Ile mRNA variant was able to partially rescue\n                    <jats:italic>vsx2<\/jats:italic>\n                    expression while p.Tyr48Asn and p.Pro201Leu mRNA variants were not. However, swimming and balance problems could not be rescued by any of these variants. These results suggest that the p.Met186Ile is a hypomorphic allele. Our work expands the genotypes and phenotypes associated with\n                    <jats:italic>ZC4H2<\/jats:italic>\n                    \u2010related disorder and demonstrates that the zebrafish system is a reliable method to determine the pathogenicity of\n                    <jats:italic>ZC4H2<\/jats:italic>\n                    variants.\n                  <\/jats:p>","DOI":"10.1111\/cge.14248","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T04:37:21Z","timestamp":1665981441000},"page":"167-178","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Expanding allelic and phenotypic spectrum of ZC4H2\u2010related disorder: A novel hypomorphic variant and high prevalence of tethered cord"],"prefix":"10.1111","volume":"103","author":[{"given":"Parith","family":"Wongkittichote","sequence":"first","affiliation":[{"name":"Division of Genetics and Genomic Medicine, Department of Pediatrics St. Louis Children's Hospital, Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae\u2010Ik","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Biology Chungnam National University  Daejeon South Korea"},{"name":"Zebrafish Center for Disease Modeling  Daejeon South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oc\u2010Hee","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biology Chungnam National University  Daejeon South Korea"},{"name":"Zebrafish Center for Disease Modeling  Daejeon South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kacie","family":"Riley","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics Duke University Medical School  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dwight","family":"Koeberl","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics Duke University Medical School  Durham North Carolina USA"},{"name":"Department of Molecular Genetics and Microbiology Duke University  North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0658-3847","authenticated-orcid":false,"given":"Vinodh","family":"Narayanan","sequence":"additional","affiliation":[{"name":"Center for Rare Childhood Disorders Translational Genomics Research Institute  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keri","family":"Ramsey","sequence":"additional","affiliation":[{"name":"Center for Rare Childhood Disorders Translational Genomics Research Institute  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Balak","sequence":"additional","affiliation":[{"name":"Center for Rare Childhood Disorders Translational Genomics Research Institute  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7770-1943","authenticated-orcid":false,"given":"Charles E.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center  Greenwood South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Cueto\u2010Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Genetics Vall d'Hebron Barcelona Hospital Campus  Barcelona Spain"},{"name":"Medicine Genetics Group, Vall Hebron Research Institute (VHIR) Vall d'Hebron Barcelona Hospital Campus, Autonomous University of Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francina Munell","family":"Casadesus","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology Hospital Vall d'Hebron  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheol\u2010Hee","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biology Chungnam National University  Daejeon South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1329-4100","authenticated-orcid":false,"given":"Marwan S.","family":"Shinawi","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomic Medicine, Department of Pediatrics St. Louis Children's Hospital, Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,10,31]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9071600"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/jmcb\/mjz087"},{"key":"e_1_2_11_4_1","doi-asserted-by":"crossref","unstructured":"KimJ ChoiTI ParkS KimMH KimCH LeeS. 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