Variant Synonymizer: Platform to identify mutations defined in different ways is available now!

VarSy

Over 2,000 gene–disease validation summaries are now available—no login required!

Browse Summaries

DEPDC5 – familial focal epilepsy with variable foci

Familial focal epilepsy with variable foci (FFEVF) is an autosomal dominant disorder characterized by focal seizures arising from different cortical regions among affected family members. DEPDC5 (HGNC:18423) encodes a key component of the GATOR1 complex that represses mTORC1 signaling.

Heterozygous DEPDC5 variants—comprising frameshift, nonsense, splice-site, and missense mutations—have been reported in at least 13 unrelated probands from over 10 families with FFEVF (PMID:23542701; PMID:30767899). Common presentations include occipital semiology in one generation and frontal or temporal lobe seizures in others, with normal neuroimaging in many individuals.

Segregation analyses demonstrate co-segregation of DEPDC5 variants across multi-generation pedigrees, accounting for 19 additional affected relatives. A representative variant is c.4718T>C (p.Leu1573Pro) identified in an Argentine family with three affected members (PMID:30767899).

Functional studies reveal that pathogenic DEPDC5 variants disrupt GATOR1 complex formation and fail to inhibit mTORC1 under amino acid deprivation. DEPdc5 knockout mice display embryonic dysmorphology, mTORC1 hyperactivation, and cortical dysplasia-like lesions (PMID:28974734). In vivo, CRISPR-Cas9 second-hit models recapitulate focal cortical dysplasia and seizures, supporting a two-hit mechanism (PMID:29708509).

These integrated genetic and experimental data definitively establish DEPDC5 as the causal gene for autosomal dominant familial focal epilepsy with variable foci. Identification of DEPDC5 mutations enables precise molecular diagnosis and suggests mTORC1 inhibitors as targeted therapy.

References

  • Epileptic disorders • 2019 • DEPDC5 mutation and familial focal epilepsy with variable foci: genotype and phenotype of a family. PMID:30767899
  • Nature Genetics • 2013 • Mutations of DEPDC5 cause autosomal dominant focal epilepsies. PMID:23542701
  • Scientific Reports • 2017 • Knockout of the epilepsy gene Depdc5 in mice causes severe embryonic dysmorphology with hyperactivity of mTORC1 signalling. PMID:28974734
  • The Journal of Clinical Investigation • 2018 • DEPDC5 takes a second hit in familial focal epilepsy. PMID:29708509

Evidence Based Scoring (AI generated)

Gene–Disease Association

Definitive

Multiple independent families (>13 probands) with obligate autosomal dominant inheritance, multi-generation segregation, and concordant functional data demonstrating mTORC1 hyperactivation and rescue by rapamycin.

Genetic Evidence

Strong

Thirteen unrelated probands from over 10 families, with heterozygous LoF and missense variants co-segregating in pedigrees (PMID:30767899; PMID:23542701).

Functional Evidence

Strong

In vitro GATOR1 complex assays and in vivo Depdc5 knockout/second-hit mouse models show mTORC1 hyperactivation and cortical dysplasia recapitulating human phenotype; rescue by rapamycin (PMID:28974734; PMID:29708509).