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

TitleSomatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy.
Publication TypeJournal Article
Year of Publication2018
AuthorsWinawer, MR, Griffin, NG, Samanamud, J, Baugh, EH, Rathakrishnan, D, Ramalingam, S, Zagzag, D, Schevon, CA, Dugan, P, Hegde, M, Sheth, SA, McKhann, GM, Doyle, WK, Grant, GA, Porter, BE, Mikati, MA, Muh, CR, Malone, CD, Bergin, AMarie R, Peters, JM, McBrian, DK, Pack, AM, Akman, CI, LaCoursiere, CM, Keever, KM, Madsen, JR, Yang, E, Lidov, HGW, Shain, C, Allen, AS, Canoll, PD, Crino, PB, Poduri, AH, Heinzen, EL
JournalAnn Neurol
Volume83
Issue6
Pagination1133-1146
Date Published2018 Jun
ISSN1531-8249
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.

DOI10.1002/ana.25243
Alternate JournalAnn. Neurol.
PubMed ID29679388
PubMed Central IDPMC6105543
Grant ListUM1 AI100645 / AI / NIAID NIH HHS / United States
P30 AG028377 / AG / NIA NIH HHS / United States
U01 NS077274 / NS / NINDS NIH HHS / United States
UM1 HG006504 / HG / NHGRI NIH HHS / United States
K01 MH098126 / MH / NIMH NIH HHS / United States
R56 AI098588 / AI / NIAID NIH HHS / United States
P50 AG008702 / AG / NIA NIH HHS / United States
R01 NS089552 / NS / NINDS NIH HHS / United States
U54 NS078059 / NS / NINDS NIH HHS / United States
P01 AG007232 / AG / NIA NIH HHS / United States
RF1 AG054023 / AG / NIA NIH HHS / United States
R01 HD048805 / HD / NICHD NIH HHS / United States
R01 NS084142 / NS / NINDS NIH HHS / United States
RC2 MH089915 / MH / NIMH NIH HHS / United States
R01 NS094596 / NS / NINDS NIH HHS / United States
U01 HG007672 / HG / NHGRI NIH HHS / United States
U01 NS053998 / NS / NINDS NIH HHS / United States
P30 HD018655 / HD / NICHD NIH HHS / United States
P01 HD080642 / HD / NICHD NIH HHS / United States
R01 MH097971 / MH / NIMH NIH HHS / United States
U01 NS077303 / NS / NINDS NIH HHS / United States
U19 AI067854 / AI / NIAID NIH HHS / United States
R01 MH099216 / MH / NIMH NIH HHS / United States
R01 AG037212 / AG / NIA NIH HHS / United States
R01 DK080099 / DK / NIDDK NIH HHS / United States
RC2 NS070344 / NS / NINDS NIH HHS / United States
U01 NS077276 / NS / NINDS NIH HHS / United States
UL1 TR000040 / TR / NCATS NIH HHS / United States
UL1 TR001873 / TR / NCATS NIH HHS / United States
R01 NS095368 / NS / NINDS NIH HHS / United States