ZFHX3 – Partial Epilepsy and Developmental Epileptic Encephalopathy

ZFHX3 encodes a zinc-finger homeobox transcription factor highly expressed during neuronal development and implicated in cell proliferation, differentiation, and death. Emerging genetic studies have linked biallelic variants in ZFHX3 to childhood partial (focal) epilepsy and developmental epileptic encephalopathy (DEE).

In a cohort of 378 individuals with focal epilepsy, whole-exome sequencing identified compound heterozygous ZFHX3 variants in eight unrelated probands (PMID:38508705) demonstrating a significant variant burden compared to controls. The inheritance mode is autosomal recessive, with no additional affected relatives reported.

The variant spectrum includes missense changes and frameshift insertions/deletions. A representative pathogenic variant is c.314C>T (p.Pro105Leu), observed in one proband, consistent with loss-of-function and altered protein function.

Clinically, all eight individuals presented with focal-onset seizures (HP:0007359). Five had mild partial epilepsy with later onset, while three developed DEE manifesting as early spasms or non-convulsive status epilepticus, yet achieved seizure freedom on antiepileptic drugs without steroids.

Functional validation in a Drosophila Zfh2 knockdown model recapitulated seizure-like behaviors and showed increased excitatory neuron firing, establishing concordant experimental evidence for pathogenicity (PMID:38508705).

The overall ClinGen clinical validity for ZFHX3 in epilepsy is Moderate based on eight unrelated probands and supportive animal model data. Genetic diagnosis of ZFHX3 variants facilitates precision therapy and prognostication in childhood focal epilepsy and DEE.

References

• Unspecified Journal | 2024 | ZFHX3 is a novel causative gene of childhood partial epilepsy and DEE PMID:38508705

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