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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Winawer, 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, AMR; 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

Published Date

  • June 2018

Published In

Volume / Issue

  • 83 / 6

Start / End Page

  • 1133 - 1146

PubMed ID

  • 29679388

Pubmed Central ID

  • PMC6105543

Electronic International Standard Serial Number (EISSN)

  • 1531-8249

Digital Object Identifier (DOI)

  • 10.1002/ana.25243


  • eng

Conference Location

  • United States