Brain somatic mutations in SLC35A2 cause intractable epilepsy with aberrant N-glycosylation

(A) Schematic figure showing brain somatic mutations in SLC35A2 identified in this study. Red star: locations of each identified mutation (B) Extracted compound chromatograms (ECCs) of N-glycans from brain tissues. EPI219 and LGS150: subjects carrying somatic mutations in SLC35A2. Control EPI166: patient with intractable focal epilepsy confirmed to have no specific somatic or germline mutations in deep WES. Control MET886 and MET344: specimens from the tumor-free margin of individuals with a metastatic tumor as part of a planned resection. These specimens were pathologically confirmed as normal brain tissue. The ECCs were color coded according to N-glycosylation types: blue for complex-type glycans containing galactose residues, red for truncated-type glycans, green for high mannose glycans, sky blue for hybrid-type glycans, and pink for the glycans involving high degrees of HexNAc residues. Pink round rectangle square: N-glycan structures showing high degrees of N-acetylglucosamine (HexNAc), such as Hex₃HexNAc₇Fuc₁ and Hex₃HexNAc₈Fuc₁ (C) Representative CID MS/MS spectrum of aberrant N-glycan Hex₃HexNAc₇Fuc₁ in the positive ion detection mode. Almost all fragment ions were single-protonated ions [M + H]+; others are indicated as a superscript. Pink square: Hex₃HexNAc₇Fuc₁ glycan, identified by collision-induced dissociation MS/MS, representing the ion at M/Z 1036.90.