Familial cortical dysplasia type IIA caused by a germline mutation in DEPDC5

Thomas Scerri; Jessica R Riseley; Greta Gillies; Kate Pope; Rosemary Burgess; Simone A Mandelstam; Leanne Dibbens; Chung W Chow; Wirginia Maixner; Anthony Simon Harvey; Graeme D Jackson; David J Amor; Martin B Delatycki; Peter B Crino; Samuel F Berkovic; Ingrid E Scheffer; Melanie Bahlo; Paul J Lockhart; Richard J Leventer

doi:10.1002/acn3.191

Familial cortical dysplasia type IIA caused by a germline mutation in DEPDC5

Ann Clin Transl Neurol. 2015 May;2(5):575-80. doi: 10.1002/acn3.191. Epub 2015 Mar 12.

Authors

Thomas Scerri¹, Jessica R Riseley², Greta Gillies², Kate Pope², Rosemary Burgess³, Simone A Mandelstam⁴, Leanne Dibbens⁵, Chung W Chow⁶, Wirginia Maixner⁷, Anthony Simon Harvey⁸, Graeme D Jackson³, David J Amor⁹, Martin B Delatycki¹⁰, Peter B Crino¹¹, Samuel F Berkovic³, Ingrid E Scheffer¹², Melanie Bahlo¹, Paul J Lockhart⁹, Richard J Leventer¹³

Affiliations

¹ Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research 1G Royal Parade, Parkville, Victoria, Australia.
² Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute Parkville, Victoria, Australia.
³ The Florey Institute of Neuroscience and Mental Health Melbourne, Australia ; Epilepsy Research Centre, University of Melbourne, Austin Health Melbourne, Australia.
⁴ The Florey Institute of Neuroscience and Mental Health Melbourne, Australia ; Department of Radiology, Royal Children's Hospital Melbourne, Australia ; Department of Radiology, University of Melbourne Melbourne, Australia.
⁵ Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia Adelaide, Australia ; Sansom Institute for Health Research, University of South Australia Adelaide, Australia.
⁶ Department of Pediatrics, University of Melbourne Melbourne, Australia ; Department of Anatomical Pathology, Royal Children's Hospital Melbourne, Australia.
⁷ Department of Neurosurgery, Royal Children's Hospital Melbourne, Australia ; Murdoch Childrens Research Institute Melbourne, Australia.
⁸ The Florey Institute of Neuroscience and Mental Health Melbourne, Australia ; Department of Pediatrics, University of Melbourne Melbourne, Australia ; Murdoch Childrens Research Institute Melbourne, Australia ; Department of Neurology, Royal Children's Hospital Melbourne, Australia.
⁹ Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute Parkville, Victoria, Australia ; Department of Pediatrics, University of Melbourne Melbourne, Australia.
¹⁰ Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute Parkville, Victoria, Australia ; Department of Pediatrics, University of Melbourne Melbourne, Australia ; Clinical Genetics, Austin Health Melbourne, Australia.
¹¹ Shriners Hospital Pediatric Research Center, Temple University Philadelphia, Pennsylvania.
¹² The Florey Institute of Neuroscience and Mental Health Melbourne, Australia ; Epilepsy Research Centre, University of Melbourne, Austin Health Melbourne, Australia ; Department of Pediatrics, University of Melbourne Melbourne, Australia ; Department of Neurology, Royal Children's Hospital Melbourne, Australia.
¹³ Department of Pediatrics, University of Melbourne Melbourne, Australia ; Murdoch Childrens Research Institute Melbourne, Australia ; Department of Neurology, Royal Children's Hospital Melbourne, Australia.

Abstract

Whole-exome sequencing of two brothers with drug-resistant, early-onset, focal epilepsy secondary to extensive type IIA focal cortical dysplasia identified a paternally inherited, nonsense variant of DEPDC5 (c.C1663T, p.Arg555*). This variant has previously been reported to cause familial focal epilepsy with variable foci in patients with normal brain imaging. Immunostaining of resected brain tissue from both brothers demonstrated mammalian target of rapamycin (mTOR) activation. This report shows the histopathological features of cortical dysplasia associated with a DEPDC5 mutation, confirms mTOR dysregulation in the malformed tissue and expands the spectrum of neurological manifestations of DEPDC5 mutations to include severe phenotypes with large areas of cortical malformation.

Grants and funding

R01 NS082343/NS/NINDS NIH HHS/United States