This report describes a form of generalized epilepsy associated with variants in the ZFHX3 gene; this form of generalized epilepsy exhibits autosomal recessive inheritance. The ZFHX3 gene encodes a transcription factor involved in myogenic and neuronal development. There is a single Drosophila gene orthologous to ZFHX3, Dmel\zfh2, for which multiple genetic reagents have been generated, including loss-of-function mutations, RNAi-targeting constructs, and overexpression constructs. Dmel\zfh2 is also orthologous to human ZFHX4 and ZFHX2.
A UAS construct of wild-type human Hsap\ZFHX3 gene has been introduced into flies, but has not been characterized.
In Drosophila, adults with RNAi-mediated knockdown of Dmel\zfh2 exhibit seizure-like behaviors in the bang-sensitivity test. Assayed in adult brain, zfh2 knockdown induces increased neural excitability in projection neurons.
[updated July 2026 by FlyBase; FBrf0222196]
Familial focal epilepsy with variable foci (FFEVF) is an uncommon form of recurrent seizures (epilepsy) that runs in families. Seizures associated with FFEVF can begin at any time from infancy to adulthood. The seizures are described as focal or partial, which means they begin in one region of the brain and do not cause a loss of consciousness. [MedlinePlus, Familial focal epilepsy with variable foci; 2025.02.19]
Familial focal epilepsy with variable foci (FFEVF) is a form of epilepsy characterized by focal seizures arising from different cortical regions, including the temporal, frontal, parietal, and occipital lobes. A subset of patients have structural brain abnormalities, particularly focal cortical dysplasia (FCD) (summary by Ricos et al., 2016; pubmed:26505888). [from MIM:617118; 2025.02.19]
Idiopathic generalized epilepsy is a broad term that encompasses several common seizure phenotypes, classically including childhood absence epilepsy (CAE, ECA; see MIM:600131), juvenile absence epilepsy (JAE, EJA; see MIM:607631), juvenile myoclonic epilepsy (JME, EJM; see MIM:254770), and epilepsy with grand mal seizures on awakening (Commission on Classification and Terminology of the International League Against Epilepsy, 1989, pubmed:2502382). These recurrent seizures occur in the absence of detectable brain lesions and/or metabolic abnormalities. Seizures are initially generalized with a bilateral, synchronous, generalized, symmetrical EEG discharge (Zara et al., 1995, pubmed:8528209; Lu and Wang, 2009,pubmed:19298753). [from MIM:600669; 2026.07.09]
[EPILEPSY, IDIOPATHIC GENERALIZED 20; EIG20](https://omim.org/entry/621500)
[ZINC FINGER HOMEOBOX 3; ZFHX3](https://omim.org/entry/104155)
Five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent non-convulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids.
Idiopathic generalized epilepsy-20 (EIG20) is an autosomal recessive seizure disorder characterized by the onset of partial epilepsy usually early in the first decade of life, although onset in the early teenage years has been reported. Seizure types evolve to include complex partial seizures and secondary generalized tonic-clonic seizures associated with focal, and sometimes diffuse, EEG abnormalities. Patients become seizure-free with antiepileptic medication, and most show normal development. Some patients with severe and frequent seizures (multiple times a day) show global developmental delay (He et al., 2024, pubmed:38508705). [from MIM:621500; 2026.07.09]
Compound heterozygous ZFHX3 variants were identified in eight unrelated cases of partial (focal) epilepsy (He et al., pubmed:38508705; FBrf0259871).
Idiopathic generalized epilepsy-20 (EIG20) is caused by compound heterozygous mutation in the ZFHX3 gene on chromosome 16q22. [from MIM:621500; 2026.07.09]
ZFHX3 encodes a transcription factor with multiple homeodomains and zinc finger motifs that regulates myogenic and neuronal differentiation. [GeneCards, ZFHX3; 2025.02.21]
ZFHX3 is a transcriptional regulator that interacts with AT motifs in target genes. ZFHX3 is involved in regulation of circadian rhythm (Parsons et al., 2015, pubmed:26232227) and appetite and body weight (Nolan et al., 2023, pubmed:37713040). [from MIM:104155; 2026.07.09]
Many to one: 3 human genes to 1 Drosophila gene.
High-scoring ortholog of ZFHX3 and ZFHX4; moderate-scoring ortholog of ZFHX2 (1 Drosophila to 3 human).
