Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
DEPDC5 encodes a component of the GATOR1 complex and has been implicated in familial focal epilepsies, particularly autosomal dominant nocturnal frontal lobe epilepsy (MONDO:0020300) through loss-of-function mechanisms. Initial genetic screening of 30 small European ADNFLE families identified splice and nonsense variants in DEPDC5 in 4 unrelated probands, accounting for 13% of cases (PMID:24814846). All identified variants—c.2355-2A>G, c.1459C>T (p.Arg487Ter), c.3259C>T (p.Arg1087Ter), and c.4107G>A (p.Trp1369Ter)—are predicted to truncate the protein or disrupt splicing, consistent with autosomal dominant inheritance and haploinsufficiency (PMID:24814846).
Segregation analysis in small multi-generation pedigrees demonstrated co-segregation of DEPDC5 variants with nocturnal frontal lobe seizures in at least 4 affected relatives across families, supporting pathogenicity and penetrance variability. Clinically, 78% of mutation carriers were drug-resistant, highlighting the refractory nature of DEPDC5-associated ADNFLE (PMID:24814846). These observations align with autosomal dominant transmission and reduced penetrance commonly seen in GATOR1-related epilepsies.
Functional assays in lymphoblastic cell lines confirmed that the nonsense variants p.Arg487Ter and p.Arg1087Ter undergo nonsense-mediated decay, leading to significant transcript loss and validating a loss-of-function mechanism (PMID:24814846). This concords with broader evidence implicating DEPDC5 haploinsufficiency in mTORC1 hyperactivation, neuronal hyperexcitability, and focal seizure phenotypes.
Collectively, genetic and experimental data satisfy ClinGen criteria for a Strong gene-disease association: multiple unrelated probands with deleterious variants, segregation in families, and robust functional concordance. Autosomal dominant inheritance with variable penetrance and drug resistance profiles underscores the clinical relevance of DEPDC5 screening in ADNFLE. Key take-home: Loss-of-function DEPDC5 variants confer a strong risk for autosomal dominant nocturnal frontal lobe epilepsy, informing genetic diagnosis and potential mTOR-targeted therapies.
Gene–Disease AssociationStrong4 unrelated probands with loss-of-function variants, segregation in multiple pedigrees, concordant NMD functional data Genetic EvidenceModerate4 loss-of-function variants in 4 probands; co-segregation in four families Functional EvidenceModerateNonsense-mediated decay assays confirm transcript degradation and loss-of-function |