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Article Abstract
Background: The PHF21A gene encodes the protein BRAF histone deacetylase complex 80 (BHC80), which is primarily expressed in the human brain and essential for neurodevelopment and seizures. However, the implications of PHF21A variants in human disease pathogenesis have yet to be fully elucidated.
Methods: Whole-exon sequencing was performed on three patients with PHF21A variants. The associated phenotype was validated using a phf21ab-knockout zebrafish model generated via CRISPR/Cas9 technology.
Results: Three patients exhibited de novo PHF21A pathogenic variants associated with infantile epileptic spasm syndrome (IESS). Notably, developmental delay was evident in all cases prior to seizure onset. One patient presented with comorbid autism spectrum disorder (ASD) and macrocephaly. Brain MRI of two patients showed widening of the frontotemporal subarachnoid space and ventriculomegaly. Following therapeutic intervention, two patients achieved seizure remission. To further elucidate the functional consequences of PHF21A deficiency, we conducted comprehensive morphological, behavioral, and electrophysiological analyses in phf21ab-knockout zebrafish model. Compared with the cas9 control group, compared with the Cas9 control group, the phf21ab knockout group exhibited significant reductions in the area of the forebrain, midbrain, and whole brain. Electrophysiological assessments revealed epileptiform discharges in 6 of 25 phf21ab-knockout zebrafish.
Conclusion: These findings collectively suggest that PHF21A pathogenic variants exert substantial impacts on neurodevelopment and seizure disorders. The observed neuroanatomical alterations and epileptogenic activity in the zebrafish model reveal an important role of PHF21A in neurodevelopment and epilepsy.
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| http://dx.doi.org/10.1016/j.neuroscience.2025.08.007 | DOI Listing |
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