Brain somatic mutations in SLC3SA2 cause intractable epilepsy with aberrant N-glycosylation

Objective To identify whether somatic mutations in SLC35A2 alter N-glycan structures in human brain tissues and cause nonlesional focal epilepsy (NLFE) or mild malformation of cortical development (mMCD). Methods Deep whole exome and targeted sequencing analyses were conducted for matched brain and blood tissues from patients with intractable NLFE and patients with mMCD who are negative for mutations in mTOR pathway genes. Furthermore, tissue glyco-capture and nanoLC/mass spectrometry analysis were performed to examine N-glycosylation in affected brain tissue. Results Six of the 31 (19.3%) study patients exhibited brain-only mutations in SLC35A2 (mostly nonsense and splicing site mutations) encoding a uridine diphosphate (UDP)-galactose transporter. Glycome analysis revealed the presence of an aberrant N-glycan series, including high degrees of N-acetylglucosamine, in brain tissues with SLC35A2 mutations. Conclusion Our study suggests that brain somatic mutations in SLC35A2 cause intractable focal epilepsy with NLFE or mMCD via aberrant N-glycosylation in the affected brain.