Role of ZFHX4 in orofacial clefting based on human genetic data and zebrafish models.

Autor: Ishorst N; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany. nina.ishorst@uni-bonn.de.; Institute of Anatomy, Division of Neuroanatomy, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany. nina.ishorst@uni-bonn.de., Hölzel S; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.; Institute of Anatomy and Cell Biology, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany., Greve C; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.; LOEWE Centre for Translational Biodiversity Genomics, Frankfurt am Main, Germany., Yilmaz Ö; Institute of Anatomy, Division of Neuroanatomy, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany., Lindenberg T; Institute of Anatomy, Division of Neuroanatomy, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany., Lambertz J; Institute of Anatomy, Division of Neuroanatomy, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany., Drichel D; Cologne Center for Genomics, University of Cologne, Cologne, Germany., Zametica B; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany., Mingardo E; Institute of Anatomy and Cell Biology, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.; Faculty of Life Science, Nutritional Biochemistry, University of Bayreuth, Bayreuth, Germany., Kalanithy JC; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.; Institute of Anatomy, Division of Neuroanatomy, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany., Channab K; Institute of Anatomy and Cell Biology, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany., Kibris D; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.; Institute of Anatomy, Division of Neuroanatomy, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany., Henne S; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany., Degenhardt F; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.; Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Duisburg, Germany., Siewert A; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany., Dixon M; Faculty of Biology, Medicine & Health, University of Manchester, Manchester, M13 9PL, UK., Kruse T; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Orthodontics, Cologne, Germany., Ongkosuwito E; Department of Dentistry, Section of Orthodontics and Craniofacial Biology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands., Girisha KM; Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India., Pande S; Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India., Nowak S; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany., Hagelueken G; Institute of Structural Biology, University of Bonn, Bonn, Germany., Geyer M; Institute of Structural Biology, University of Bonn, Bonn, Germany., Carels C; Department of Human Genetics, KU Leuven, Leuven, Belgium., van Rooij IALM; IQ Health Science Department, Radboud University Medical Center, Nijmegen, The Netherlands., Ludwig KU; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany., Odermatt B; Institute of Anatomy, Division of Neuroanatomy, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany. b.odermatt@uni-bonn.de.; Institute of Anatomy and Cell Biology, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany. b.odermatt@uni-bonn.de., Mangold E; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany. e.mangold@uni-bonn.de.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2024 Dec 19. Date of Electronic Publication: 2024 Dec 19.
DOI: 10.1038/s41431-024-01775-9
Abstrakt: 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.
Competing Interests: Competing interests: For the sake of completeness, we declare that D.D. provides compensated consulting services outside of academia as an independent consultant. Furthermore, K.U.L. is a co-founder of LAMPseq Diagnostics GmbH. Although past and current clients might include biotech, life science, and pharma companies, the services are not related to the presented work and all authors are unaware of any possible competing interests. Ethical approval: Written informed consent was obtained from all participants, or the respective parents/legal guardians, prior to inclusion. The study was approved by the ethics committee of the Medical Faculty of the University of Bonn (ethics approval number 295/14, last dated June 20th, 2022). Animal husbandry and experimental setups were in accordance with European Legislation for the Protection of Animals used for Scientific Purposes (Directive 2010/62/EU). National law exempts all zebrafish experiments conducted at larval stages up to 5 dpf, before larvae begin to feed, from ethical approval.
(© 2024. The Author(s).)
Databáze: MEDLINE
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