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Ann Neurol. 2018 Jun;83(6):1133-1146. doi: 10.1002/ana.25243. Epub 2018 May 16.

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

Author information

1
Gertrude H. Sergievsky Center, Columbia University, New York, NY.
2
Department of Neurology, Columbia University, New York, NY.
3
Institute for Genomic Medicine, Columbia University, New York, NY.
4
Department of Neurosurgery, Columbia University, New York Presbyterian Hospital, New York, NY.
5
Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD.
6
Department of Pathology, New York University Langone Medical Center, New York, NY.
7
Department of Neurosurgery, New York University Langone Medical Center, New York, NY.
8
Department of Neurology, New York University Langone Medical Center, New York, NY.
9
Department of Neurology, University of California, San Francisco, San Francisco, CA.
10
Department of Neurological Surgery, Columbia University, New York, NY.
11
Department of Neurosurgery, Lucile Packard Children's Hospital at Stanford, Stanford, CA.
12
Department of Neurology, Lucile Packard Children's Hospital at Stanford, Stanford, CA.
13
Division of Pediatric Neurology, Duke University Medical Center, Durham, NC.
14
Department of Neurobiology, Duke University, Durham, NC.
15
Department of Neurosurgery, Duke University Medical Center, Durham, NC.
16
Department of Neurology, Harvard Medical School, Boston, MA.
17
Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA.
18
Division of Pediatric Neurology, Columbia University, New York, NY.
19
Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA.
20
Department of Neurology, Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA.
21
Department of Neurosurgery, Boston Children's Hospital and Department of Neurosurgery, Harvard Medical School, Boston, MA.
22
Department of Radiology, Boston Children's Hospital and Department of Radiology, Harvard Medical School, Boston, MA.
23
Department of Pathology, Boston Children's Hospital and Department of Pathology, Harvard Medical School, Boston, MA.
24
Department of Biostatistics and Bioinformatics, Duke University, Durham, NC.
25
Department of Pathology and Cell Biology, Columbia University, New York, NY.
26
F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA.

Abstract

OBJECTIVE:

Somatic 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.

METHODS:

We 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.

RESULTS:

We 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.

INTERPRETATION:

We 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.

PMID:
29679388
PMCID:
PMC6105543
[Available on 2019-06-01]
DOI:
10.1002/ana.25243

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