Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy.
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Winawer Melodie R, Griffin Nicole G, Samanamud Jorge, Baugh Evan H, Rathakrishnan Dinesh, Ramalingam Senthilmurugan, Zagzag David, Schevon Catherine A, Dugan Patricia, Hegde Manu, Sheth Sameer A, McKhann Guy M, Doyle Werner K, Grant Gerald A, Porter Brenda E, Mikati Mohamad A, Muh Carrie R, Malone Colin D, Bergin Ann Marie R, Peters Jurriaan M, McBrian Danielle K, Pack Alison M, Akman Cigdem I, LaCoursiere Christopher M, Keever Katherine M, Madsen Joseph R, Yang Edward, Lidov Hart G W, Shain Catherine, Allen Andrew S, Canoll Peter D, Crino Peter B, Poduri Annapurna H, Heinzen Erin L
Аннотация
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.