{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Ishorst N"],"funding":["Else Kröner-Fresenius-Stiftung (Else Kroner-Fresenius Foundation)","Deutsche Forschungsgemeinschaft","Deutsche Forschungsgemeinschaft (German Research Foundation)","Else Kröner-Fresenius-Stiftung","DBT/Wellcome Trust India Alliance","Wellcome Trust"],"pagination":["595-606"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7617551"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["33(5)"],"pubmed_abstract":["Orofacial clefting (OFC) is a frequent congenital anomaly and can occur either in the context of underlying syndromes or in isolation (nonsyndromic). The two common OFC phenotypes are cleft lip with/without cleft palate (CL/P) and cleft palate only (CPO). In this study, we searched for penetrant CL/P genes, by evaluating de novo copy number variants (CNV) from an exome sequencing dataset of 50 nonsyndromic patient-parent trios. We detected a heterozygous 86 kb de novo deletion affecting exons 4-11 of ZFHX4, a gene previously associated with OFC. Genetic and phenotypic data from our in-house and the AGORA cohort (710 and 229 individuals with nonsyndromic CL/P) together with literature and database reviews demonstrate that ZFHX4 variants can lead to both nonsyndromic and syndromic forms not only of CL/P but also CPO. Expression analysis in published single-cell RNA-sequencing data (mouse embryo, zebrafish larva) at relevant time-points support an important role of Zfhx4/zfhx4 in craniofacial development. To characterize the role of zfhx4 in zebrafish craniofacial development, we knocked out/down the zebrafish orthologue. Cartilage staining of the zfhx4 CRISPR F0 knockout and morpholino knockdown at 4 days post-fertilization showed an underdeveloped and abnormally shaped ethmoid plate and cartilaginous jaw (resembling micrognathia). While there is evidence for the dominant inheritance of ZFHX4 variants in OFC, we here present a patient with a possible recessive inheritance. In conclusion, ZFHX4 has a highly heterogeneous phenotypic spectrum and variable mode of inheritance. Our data highlight that ZFHX4 should be considered in genetic testing in patients with nonsyndromic clefting."],"journal":["European journal of human genetics : EJHG"],"pubmed_title":["Role of ZFHX4 in orofacial clefting based on human genetic data and zebrafish models."],"pmcid":["PMC7617551"],"funding_grant_id":["Q-614.1254","MA 2546/5-1","LU 1944/2-1","IA/CRC/20/1/600002"],"pubmed_authors":["Henne S","Ludwig KU","Pande S","Kibris D","Girisha KM","Ishorst N","Zametica B","Drichel D","Mingardo E","Lambertz J","Holzel S","Ongkosuwito E","Siewert A","Odermatt B","Channab K","Nowak S","Geyer M","Mangold E","Degenhardt F","Dixon M","Greve C","Yilmaz O","Carels C","Lindenberg T","Kalanithy JC","Kruse T","van Rooij IALM","Hagelueken G"],"additional_accession":[]},"is_claimable":false,"name":"Role of ZFHX4 in orofacial clefting based on human genetic data and zebrafish models.","description":"Orofacial clefting (OFC) is a frequent congenital anomaly and can occur either in the context of underlying syndromes or in isolation (nonsyndromic). The two common OFC phenotypes are cleft lip with/without cleft palate (CL/P) and cleft palate only (CPO). In this study, we searched for penetrant CL/P genes, by evaluating de novo copy number variants (CNV) from an exome sequencing dataset of 50 nonsyndromic patient-parent trios. We detected a heterozygous 86 kb de novo deletion affecting exons 4-11 of ZFHX4, a gene previously associated with OFC. Genetic and phenotypic data from our in-house and the AGORA cohort (710 and 229 individuals with nonsyndromic CL/P) together with literature and database reviews demonstrate that ZFHX4 variants can lead to both nonsyndromic and syndromic forms not only of CL/P but also CPO. Expression analysis in published single-cell RNA-sequencing data (mouse embryo, zebrafish larva) at relevant time-points support an important role of Zfhx4/zfhx4 in craniofacial development. To characterize the role of zfhx4 in zebrafish craniofacial development, we knocked out/down the zebrafish orthologue. Cartilage staining of the zfhx4 CRISPR F0 knockout and morpholino knockdown at 4 days post-fertilization showed an underdeveloped and abnormally shaped ethmoid plate and cartilaginous jaw (resembling micrognathia). While there is evidence for the dominant inheritance of ZFHX4 variants in OFC, we here present a patient with a possible recessive inheritance. In conclusion, ZFHX4 has a highly heterogeneous phenotypic spectrum and variable mode of inheritance. Our data highlight that ZFHX4 should be considered in genetic testing in patients with nonsyndromic clefting.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 May","modification":"2026-04-08T19:51:13.125Z","creation":"2025-07-06T03:05:45.622Z"},"accession":"S-EPMC7617551","cross_references":{"pubmed":["39702590"],"doi":["10.1038/s41431-024-01775-9"]}}