Pérez Baca, María Del Rocío;
Palomares-Bralo, María;
Vanhooydonck, Michiel;
Hamerlinck, Lisa;
D'haene, Eva;
Leimbacher, Sebastian;
Jacobs, Eva Z;
... Vergult, Sarah; + view all
(2025)
Loss of function of the zinc finger homeobox 4 gene, ZFHX4, underlies a neurodevelopmental disorder.
AJHG: American Journal of Human Genetics
, 112
(6)
pp. 1388-1414.
10.1016/j.ajhg.2025.04.008.
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Abstract
8q21.11 microdeletions involving ZFHX4 have previously been associated with a syndromic form of intellectual disability, hypotonia, unstable gait, and hearing loss. We report on 63 individuals—57 probands and 6 affected family members—with protein-truncating variants (n = 41), (micro)deletions (n = 21), or an inversion (n = 1) affecting ZFHX4. Probands display variable developmental delay and intellectual disability, distinctive facial characteristics, morphological abnormalities of the central nervous system, behavioral alterations, short stature, hypotonia, and occasionally cleft palate and anterior segment dysgenesis. The phenotypes associated with 8q21.11 microdeletions and ZFHX4 intragenic loss-of-function (LoF) variants largely overlap, although leukocyte-derived DNA shows a mild common methylation profile for (micro)deletions. ZFHX4 shows increased expression during human brain development and neuronal differentiation. Furthermore, ZFHX4-interacting factors identified via immunoprecipitation followed by mass spectrometry (IP-MS) suggest an important role for ZFHX4 in cellular pathways, especially during histone modifications, protein trafficking, signal transduction, cytosolic transport, and development. Additionally, using CUT&RUN, we observed that ZFHX4 binds the promoter of genes with crucial roles in embryonic, neuronal, and axonal development. Moreover, we investigated whether the disruption of zfhx4 causes craniofacial abnormalities in zebrafish. First-generation (F0) zfhx4 crispant zebrafish, a (mosaic) mutant for zfhx4 LoF variants, have significantly shorter Meckel’s cartilage and smaller ethmoid plates compared to control zebrafish. Behavioral assays showed a decreased movement frequency in the zfhx4 crispant zebrafish in comparison with controls. Furthermore, structural abnormalities were found in the zebrafish hindbrain. In conclusion, our findings delineate a ZFHX4-associated neurodevelopmental disorder and suggest a role for zfhx4 in facial skeleton patterning, palatal development, and behavior.
| Type: | Article |
|---|---|
| Title: | Loss of function of the zinc finger homeobox 4 gene, ZFHX4, underlies a neurodevelopmental disorder |
| Location: | United States |
| DOI: | 10.1016/j.ajhg.2025.04.008 |
| Publisher version: | https://doi.org/10.1016/j.ajhg.2025.04.008 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | ZFHX4; transcription factor; neurodevelopmental disorder; 8q21.11; microdeletion; methylation profile; transcription regulation; neurogenesis; orofacial cleft; craniofacial development; ocular anomalies |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10210055 |
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