Journal article

Second-hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA

Wei Shern Lee, Sarah EM Stephenson, Katherine B Howell, Kate Pope, Greta Gillies, Alison Wray, Wirginia Maixner, Simone A Mandelstam, Samuel F Berkovic, Ingrid E Scheffer, Duncan MacGregor, Anthony Simon Harvey, Paul J Lockhart, Richard J Leventer

Annals of Clinical and Translational Neurology | WILEY | Published : 2019


Focal cortical dysplasia (FCD) causes drug-resistant epilepsy and is associated with pathogenic variants in mTOR pathway genes. How germline variants cause these focal lesions is unclear, however a germline + somatic "2-hit" model is hypothesized. In a boy with drug-resistant epilepsy, FCD, and a germline DEPDC5 pathogenic variant, we show that a second-hit DEPDC5 variant is limited to dysmorphic neurons, and the somatic mutation load correlates with both dysmorphic neuron density and the epileptogenic zone. These findings provide new insights into the molecular and cellular correlates of FCD determining drug-resistant epilepsy and refine conceptualization of the epileptogenic zone.


Awarded by Australian Government National Health and Medical Research Council

Funding Acknowledgements

The authors thank Michael Wilson, Gemma L Carvill, and Heather C Mefford for their contributions. This work was supported by the Australian Government National Health and Medical Research Council GNT1128933, the Murdoch Children's Research Institute, the Campbell Edwards Trust, and the Brain Foundation. Additional funding was provided by the Independent Research Institute Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Program. RJL and KBH are supported by the Melbourne Children's Clinician Scientist Fellowship scheme. We thank the family for agreeing to be part of this research study.