Insights Into DEPDC5-Related Epilepsy From 586 People: Variant Penetrance, Phenotypic Spectrum, and Treatment...

DEPDC5 variants are the most common genetic cause of focal epilepsy, often linked to focal cortical dysplasia. Despite their clinical significance, up-to-date penetrance estimates and comprehensive genotype-phenotype correlations remain limited, particularly in diverse populations. This study synthesizes data from a large cohort, including reports from Asian populations, aiming to refine penetrance estimates and to identify genotype-phenotype correlations and outcomes to inform precision care in DEPDC5-related epilepsy in diverse patient populations.

Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews framework, we conducted a scoping review of PubMed for studies on "DEPDC5" published through August 2024. Studies in English, reporting genotype and phenotype information on families with DEPDC5 variants, were included; individual or sporadic cases, duplicates, and reports of recessive inheritance were excluded. Non-neurologic or nongenetic studies were excluded. Age-specific penetrance was calculated. Clinical characteristics were analyzed across individuals affected by DEPDC5-related epilepsy using the Fisher exact test and the Wilcoxon rank-sum test.

Thirty-three publications comprising 170 families, 63.5% of which were of European ethnicity, and 586 variant carriers were included. By age 10, 76.1% of variant carriers developed epilepsy, with a cumulative penetrance of 64.9% (n = 380/586, 95% CI 60.8%-68.7%). Drug resistance occurred in 48.3% of cases, and cortical malformations were present in 28% of those with available MRI. Sudden unexpected death in epilepsy accounted for 16% (n = 4/25) of deaths among affected individuals. Early seizure onset strongly correlated with drug resistance (p = 2.4e-08, W = 2,220.5, median = 1.33 vs 7), intellectual disability (p = 2.1e-08, W = 1,525.5, median = 0.9 vs 7), and lesional MRI (p = 2.2e-08, W = 4,914.5, median = 0.5 vs 7). Among drug-resistant individuals undergoing surgery (34.7% [n = 35/101]), 88% achieved favorable outcomes (Engel I or II).

By assembling the largest pooled cohort to date and including underrepresented populations, this study refines penetrance estimates and highlights the clinical severity linked to earlier seizure onset. The positive outcomes after epilepsy surgery observed in our review underscore the importance of early genetic testing and counseling, and tailored therapeutic approaches, including consideration of early surgical intervention, particularly for children with early-onset DEPDC5-related epilepsy. This retrospective review is limited to available genotype and phenotype information from families at the time of publication.