Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy

被引：102

作者：

Winawer, Melodie R. ^{[1
,2
]}

Griffin, Nicole G. ^{[3
]}

Samanamud, Jorge ^{[4
]}

Baugh, Evan H. ^{[3
]}

Rathakrishnan, Dinesh ^{[1
]}

Ramalingam, Senthilmurugan ^{[5
]}

Zagzag, David ^{[6
,7
]}

Schevon, Catherine A. ^{[2
]}

Dugan, Patricia ^{[8
]}

Hegde, Manu ^{[9
]}

Sheth, Sameer A. ^{[10
]}

McKhann, Guy M. ^{[10
]}

Doyle, Werner K. ^{[7
]}

Grant, Gerald A. ^{[11
]}

Porter, Brenda E. ^{[12
]}

Mikati, Mohamad A. ^{[13
,14
]}

Muh, Carrie R. ^{[15
]}

Malone, Colin D. ^{[3
]}

Bergin, Ann Marie R. ^{[16
,17
]}

Peters, Jurriaan M. ^{[16
,17
]}

McBrian, Danielle K. ^{[18
]}

Pack, Alison M. ^{[2
]}

Akman, Cigdem I. ^{[18
]}

LaCoursiere, Christopher M. ^{[19
]}

Keever, Katherine M. ^{[20
]}

Madsen, Joseph R. ^{[21
,22
]}

Yang, Edward ^{[23
,24
]}

Lidov, Hart G. W. ^{[25
,26
]}

Shain, Catherine ^{[19
]}

Allen, Andrew S. ^{[27
]}

Canoll, Peter D. ^{[28
]}

Crino, Peter B. ^{[5
]}

Poduri, Annapurna H. ^{[16
,17
,19
,29
]}

Heinzen, Erin L. ^{[3
,28
]}

机构：

[1] Columbia Univ, Gertrude H Sergievsky Ctr, New York, NY 10027 USA

[2] Columbia Univ, Dept Neurol, New York, NY USA

[3] Columbia Univ, Inst Genom Med, 630 West 168th St,Rm 11-401B, New York, NY 10032 USA

[4] Columbia Univ, New York Presbyterian Hosp, Dept Neurosurg, New York, NY USA

[5] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA

[6] NYU, Dept Pathol, Langone Med Ctr, 550 1St Ave, New York, NY 10016 USA

[7] NYU, Dept Neurosurg, Langone Med Ctr, 550 1St Ave, New York, NY 10016 USA

[8] NYU, Dept Neurol, Langone Med Ctr, New York, NY 10016 USA

[9] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA

[10] Columbia Univ, Dept Neurol Surg, New York, NY USA

[11] Lucile Packard Childrens Hosp, Dept Neurosurg, Stanford, CA USA

[12] Lucile Packard Childrens Hosp, Dept Neurol, Stanford, CA USA

[13] Duke Univ, Div Pediat Neurol, Med Ctr, Durham, NC USA

[14] Duke Univ, Dept Neurobiol, Durham, NC USA

[15] Duke Univ, Dept Neurosurg, Med Ctr, Durham, NC USA

[16] Harvard Med Sch, Dept Neurol, Boston, MA USA

[17] Boston Childrens Hosp, Div Epilepsy & Clin Neurophysiol, Dept Neurol, Boston, MA USA

[18] Columbia Univ, Div Pediat Neurol, New York, NY USA

[19] Boston Childrens Hosp, Dept Neurol, Epilepsy Genet Program, Boston, MA USA

[20] Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Translat Neurosci Ctr, Boston, MA USA

[21] Boston Childrens Hosp, Dept Neurosurg, Boston, MA USA

[22] Harvard Med Sch, Dept Neurosurg, Boston, MA USA

[23] Boston Childrens Hosp, Dept Radiol, Boston, MA USA

[24] Harvard Med Sch, Dept Radiol, Boston, MA USA

[25] Boston Childrens Hosp, Dept Pathol, Boston, MA USA

[26] Harvard Med Sch, Dept Pathol, Boston, MA USA

[27] Duke Univ, Dept Biostat & Bioinformat, Durham, NC USA

[28] Columbia Univ, Dept Pathol & Cell Biol, New York, NY USA

[29] Boston Childrens Hosp, FM Kirby Neurobiol Ctr, Boston, MA USA

来源：

ANNALS OF NEUROLOGY | 2018年 / 83卷 / 06期

关键词：

FOCAL CORTICAL DYSPLASIA; DE-NOVO MUTATIONS; TEMPORAL-LOBE EPILEPSY; MAMMALIAN TARGET; DEPDC5; MUTATIONS; PATHWAY; MALFORMATIONS; GENE; ENCEPHALOPATHY; CLASSIFICATION;

D O I：

10.1002/ana.25243

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

ObjectiveSomatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including nonlesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD. MethodsWe identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD. ResultsWe observed somatic variants in 5 cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in resected brain, and absent from leukocytes, in 3 of 18 individuals (17%) with NLFE, 1 female and 2 males, with variant allele frequencies (VAFs) in brain-derived DNA of 2 to 14%. Pathologic evaluation revealed focal cortical dysplasia type Ia (FCD1a) in 2 of the 3 NLFE cases. In the MCD cohort, nonsynonymous variants in SCL35A2 were detected in the brains of 2 males with intractable epilepsy, developmental delay, and magnetic resonance imaging suggesting FCD, with VAFs of 19 to 53%; Evidence for FCD was not observed in either brain tissue specimen. InterpretationWe report somatic variants in SLC35A2 as an explanation for a substantial fraction of NLFE, a largely unexplained condition, as well as focal MCD, previously shown to result from somatic mutation but until now only in PI3K-AKT-mTOR pathway genes. Collectively, our findings suggest a larger role than previously recognized for glycosylation defects in the intractable epilepsies. Ann Neurol 2018

引用

页码：1133 / 1146

页数：14

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