A zebrafish model unravels the role of PHF21A in neurodevelopment and epilepsy.

Researchers studied a gene called PHF21A in three children with severe early epilepsy and developmental delays. One child also had autism. Using a zebrafish model, they found that when this gene doesn't work properly, it causes smaller brain development and seizure-like activity. Two children's seizures improved with treatment. This research helps us understand how certain genetic changes can cause both developmental problems and epilepsy.

This study examined PHF21A gene variants in three patients with infantile epileptic spasm syndrome (IESS) and validated findings using a zebrafish knockout model. All patients showed developmental delays before seizure onset, with one presenting comorbid autism spectrum disorder and macrocephaly. Brain imaging revealed structural abnormalities including widening of frontotemporal subarachnoid space and ventriculomegaly. The zebrafish model demonstrated significant brain volume reductions across forebrain, midbrain, and whole brain regions, with epileptiform discharges observed in 24% of knockout fish.

Two patients achieved seizure remission following therapeutic intervention. These findings suggest PHF21A variants substantially impact neurodevelopment and contribute to seizure disorders through disrupted brain structure and function.

PHF21A variants may represent a novel genetic cause of early infantile epilepsy with developmental delays. Clinicians should consider genetic testing including PHF21A in cases of infantile spasms with developmental concerns. The association with autism features warrants further investigation and potential screening.

Very small patient sample (n=3) limits generalizability. Zebrafish model findings may not fully translate to human neurodevelopment. Long-term outcomes and treatment responses not extensively characterized. Mechanism of action remains unclear.

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. 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.

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.

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.