PUBLICATION
Role of ZFHX4 in orofacial clefting based on human genetic data and zebrafish models
- Authors
- Ishorst, N., Hölzel, S., Greve, C., Yilmaz, Ö., Lindenberg, T., Lambertz, J., Drichel, D., Zametica, B., Mingardo, E., Kalanithy, J.C., Channab, K., Kibris, D., Henne, S., Degenhardt, F., Siewert, A., Dixon, M., Kruse, T., Ongkosuwito, E., Girisha, K.M., Pande, S., Nowak, S., Hagelueken, G., Geyer, M., Carels, C., van Rooij, I.A.L.M., Ludwig, K.U., Odermatt, B., Mangold, E.
- ID
- ZDB-PUB-241220-1
- Date
- 2024
- Source
- European journal of human genetics : EJHG : (Journal)
- Registered Authors
- Ishorst, Nina, Lindenberg, Tobias, Odermatt, Benjamin
- Keywords
- none
- MeSH Terms
-
- Female
- Disease Models, Animal
- DNA Copy Number Variations
- Zebrafish/genetics
- Mice
- Phenotype
- Humans
- Cleft Lip*/genetics
- Cleft Lip*/pathology
- Male
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Animals
- Cleft Palate*/genetics
- Cleft Palate*/pathology
- PubMed
- 39702590 Full text @ Eur. J. Hum. Genet.
Citation
Ishorst, N., Hölzel, S., Greve, C., Yilmaz, Ö., Lindenberg, T., Lambertz, J., Drichel, D., Zametica, B., Mingardo, E., Kalanithy, J.C., Channab, K., Kibris, D., Henne, S., Degenhardt, F., Siewert, A., Dixon, M., Kruse, T., Ongkosuwito, E., Girisha, K.M., Pande, S., Nowak, S., Hagelueken, G., Geyer, M., Carels, C., van Rooij, I.A.L.M., Ludwig, K.U., Odermatt, B., Mangold, E. (2024) Role of ZFHX4 in orofacial clefting based on human genetic data and zebrafish models. European journal of human genetics : EJHG. :.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping