Insights into DEPDC5-Related Epilepsy from 586 people: Variant Penetrance, Phenotypic Spectrum, and Treatment Outcomes

Abstract

Variants in the GATOR1 complex gene DEPDC5 disrupt mTORC1 pathway regulation, driving cortical malformations and focal epilepsy. DEPDC5 is the most common genetic cause of focal epilepsy, often linked to focal cortical dysplasia (FCD). However, reduced penetrance complicates genetic counselling and risk prediction. This study analysed the largest DEPDC5-related epilepsy cohort, synthesising data from 170 families and 586 variant carriers. Epilepsy penetrance was estimated at 64.9% (n=380/586), with median seizure onset at 5 years. By age 10, 76.1% of individuals experienced seizures. Drug resistance occurred in 48.3% (n=101/209) of cases, and cortical malformations were present in 28% (n= 49/175) of MRIs. SUDEP accounted for 16% (n= 4/25) of deaths among affected individuals. Early seizure onset correlated strongly with drug resistance, intellectual disability, and MRI abnormalities, underscoring its role as a severity marker. Surgical intervention in drug-resistant cases (34.7% [n= 35/101]) achieved favourable outcomes (Engel I or II) in 88% (n= 29/33) of individuals, with pathology confirming cortical malformations in 92.6% (n=25/27) of those with abnormal MRIs. This study advances the understanding of DEPDC5-related epilepsy, providing critical insights into penetrance, phenotype, and treatment outcomes to inform precision care and genetic counselling.