Epileptic spasms are a feature of DEPDC5 mTORopathy

Abstract

Objective: To assess the presence of DEPDC5 mutations in a cohort of patients with epileptic spasms.

Methods: We performed DEPDC5 resequencing in 130 patients with spasms, segregation analysis of variants of interest, and detailed clinical assessment of patients with possibly and likely pathogenic variants.

Results: We identified 3 patients with variants in DEPDC5 in the cohort of 130 patients with spasms. We also describe 3 additional patients with DEPDC5 alterations and epileptic spasms: 2 from a previously described family and a third ascertained by clinical testing. Overall, we describe 6 patients from 5 families with spasms and DEPDC5 variants; 2 arose de novo and 3 were familial. Two individuals had focal cortical dysplasia. Clinical outcome was highly variable.

Conclusions: While recent molecular findings in epileptic spasms emphasize the contribution of de novo mutations, we highlight the relevance of inherited mutations in the setting of a family history of focal epilepsies. We also illustrate the utility of clinical diagnostic testing and detailed phenotypic evaluation in characterizing the constellation of phenotypes associated with DEPDC5 alterations. We expand this phenotypic spectrum to include epileptic spasms, aligning DEPDC5 epilepsies more with the recognized features of other mTORopathies.

Figure 1. Pedigrees of families with DEPDC5 variants and epileptic spasms

We describe 6 patients in 5 families with DEPDC5 variants and spasms. Variants arose de novo in 2 cases (families A and C) and were inherited in 3 (families B, D, and E).

Figure 2. Distribution of DEPDC5 variants in patients and controls

Upper panel of the schematic shows all previously reported truncating mutations (black)^,, and those described in this study (red). Lower panel shows all missense mutations in previous studies (black) and those described in this study (red), numbers in parentheses show the highest population MAF from the ExAC data set, and black lines show the missense variants present in ExAC and variable frequencies. Many of the missense mutations described in patients are present at appreciable frequencies in controls, and there are many missense variants across the gene. It will be vital to perform functional experiments to test the functional effect of these variants, to understand whether and how they cause disease, and to understand the incomplete penetrance that is a common feature of this disorder. ExAC = Exome Aggregation Consortium; MAF = minor allele frequency.