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

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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
Funding Information
  • NIH (R01‐NS089552, R01‐NS094596)
  • Intellectual and Developmental Disabilities Research Center (NIH P30HD018655)
  • Biogen
  • Gilead Sciences
  • UCB
  • National Institute of Neurological Disorders and Stroke (RC2NS070344, RC2MH089915, U01NS077303, U01NS053998, U54NS078059, P01HD080642)
  • National Human Genome Research Institute (UM1HG006504, U01HG007672)
  • NIH (K01MH098126, R01MH097971, R01MH099216)
  • NIH (R01DK080099)
  • NIH (1R56AI098588‐01A1)
  • NIH (UM1AI100645, U19AI067854)
  • National Center for Advancing Translational Sciences (UL1TR000040)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD048805)
  • Bill and Melinda Gates Foundation
  • Muscular Dystrophy Association
  • NIH (PO1AG07232, R01AG037212, RF1AG054023, P30AG028377)
  • NIH (UL1TR001873)
  • NIH (P50AG008702)

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