@article{01JVS3RKJS16EEP2M7Y8M2MFVM,
  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.}},
  author       = {{Pérez Baca, Maria del Rocio and Palomares-Bralo, María and Vanhooydonck, Michiel and Hamerlinck, Lisa and D'haene, Eva and Leimbacher, Sebastian and Jacobs, Eva and De Cock, Laurenz and D'haenens, Erika and Dheedene, Annelies and Malfait, Zoë and Vantomme, Lies and Silva, Ananilia and Rooney, Kathleen and Zhao, Xiaonan and Saeidian, Amir Hossein and Owen, Nichole Marie and Santos-Simarro, Fernando and Lleuger-Pujol, Roser and García-Miñaúr, Sixto and Losantos-García, Itsaso and Menten, Björn and Gestri, Gaia and Ragge, Nicola and Scott, Abbey and Iglesias, Alejandro and McConkie-Rosell, Allyn and Kritzer, Amy and Boto, Ana and Lewis, Andi M. and Tzschach, Andreas and Nicosia, Annarita and O’Donnell-Luria, Anne and Peron, Angela and Thuresson, Ann-Charlotte and Vulto-van-Silfhout, Anneke and Novelli, Antonio and Plomp, Astrid S. and Gangaram, Balram and Gil-Fournier, Belén and Keren, Boris and Genetti, Casie and De Luca, Chiara and Schaaf, Christian P. and Beneteau, Claire and Graziani, Daniela and Scott, Daryl A. and Koolen, David A. and Geneviéve, David and Bax, Dorine and Leslie, Elizabeth J. and Mizerik, Elizabeth and Roeder, Elizabeth and Magness, Emily and Nibbeling, Esther and Lesca, Gaetan and Annerén, Göran and Enns, Gregory M. and Van Esch, Hilde and Goel, Himanshu and Quintela, Inés and Cobben, Jan and Morrison, Jennifer L. and Eiris, Jesus and Stoler, Joan and Gao, Josephine and Steindl, Katharina and Dipple, Katrina and Kolokotronis, Konstantinos and Seaver, Laurie H. and Pollack, Lynda and Motazacker, Mahdi and Gasparri, Manuela and Sinnema, Margje and Digilio, Maria Cristina and McDonald, Marie T. and Ramírez, Marisol Ibarra and Doco-Fenzy, Martine and Kucharczyk, Marzena and Nizon, Mathilde and Boothe, Megan and O'Leary, Melanie C. and Carter, Melissa T. and Ross, Meredith and Wilson, Meredith and Klaassens, Merel and Ginevrino, Monia and Wojcik, Monica Hsiung and Robin, Nathaniel and Chatron, Nicolas and Boute, Odile and Agrawal, Pankaj and Fontana, Paolo and Zanoni, Paolo and Joset, Pascal and Torring, Pernille M. and Billie Au, Ping Yee and Stevens, Servi and León, Soraya Ramiro and Baskin, Stephanie and DiTroia, Stephanie Parker and Siow, Sue-Faye and Demaret, Tanguy and Plaiasu, Vasilica and Clowes, Virginia and Luo, Xi and Hilhorst-Hofstee, Yvonne and Sadikovic, Bekim and Bogaert, Elke and Vleminckx, Kris and Naert, Thomas and Syx, Delfien and Callewaert, Bert and Vergult, Sarah and ZFHX4 consortium, [missing]}},
  issn         = {{0002-9297}},
  journal      = {{AMERICAN JOURNAL OF HUMAN GENETICS}},
  keywords     = {{ZFHX4,transcription factor,neurodevelopmental disorder,8q21.11 microdeletion,methylation profile,transcription regulation,neurogenesis,orofacial cleft,craniofacial development,ocular anomalies,DE-NOVO,CRANIOFACIAL DEVELOPMENT,8Q21.11 MICRODELETION,MASS-SPECTROMETRY,READ ALIGNMENT,GENE,PROTEIN,MUTATIONS,IDENTIFICATION,MECHANISMS}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{1388--1414}},
  title        = {{Loss of function of the zinc finger homeobox 4 gene, ZFHX4, underlies a neurodevelopmental disorder}},
  url          = {{http://doi.org/10.1016/j.ajhg.2025.04.008}},
  volume       = {{112}},
  year         = {{2025}},
}

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