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

Abstract 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,...

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Main Authors:	Wei Shern Lee, Sarah E. M. 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
Format:	Article
Language:	English
Published:	Wiley 2019-07-01
Series:	Annals of Clinical and Translational Neurology
Online Access:	https://doi.org/10.1002/acn3.50815

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spelling	doaj-9a324a5ce8934bbc85b57f18d8559bdd2021-05-02T13:59:55ZengWileyAnnals of Clinical and Translational Neurology2328-95032019-07-01671338134410.1002/acn3.50815Second‐hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIAWei Shern Lee0Sarah E. M. Stephenson1Katherine B. Howell2Kate Pope3Greta Gillies4Alison Wray5Wirginia Maixner6Simone A. Mandelstam7Samuel F. Berkovic8Ingrid E. Scheffer9Duncan MacGregor10Anthony Simon Harvey11Paul J. Lockhart12Richard J. Leventer13Murdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaUniversity of Melbourne Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaAbstract 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.https://doi.org/10.1002/acn3.50815
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Wei Shern Lee Sarah E. M. 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
spellingShingle	Wei Shern Lee Sarah E. M. 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 Second‐hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA Annals of Clinical and Translational Neurology
author_facet	Wei Shern Lee Sarah E. M. 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
author_sort	Wei Shern Lee
title	Second‐hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA
title_short	Second‐hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA
title_full	Second‐hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA
title_fullStr	Second‐hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA
title_full_unstemmed	Second‐hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA
title_sort	second‐hit depdc5 mutation is limited to dysmorphic neurons in cortical dysplasia type iia
publisher	Wiley
series	Annals of Clinical and Translational Neurology
issn	2328-9503
publishDate	2019-07-01
description	Abstract 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.
url	https://doi.org/10.1002/acn3.50815
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Second‐hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA

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