De Novo Mutations in SLC35A2 Encoding a UDP-Galactose Transporter Cause Early-Onset Epileptic Encephalopathy

Early-onset epileptic encephalopathies (EOEE) are severe neurological disorders characterized by frequent seizures accompanied by developmental re- gression or retardation. Whole-exome sequencing of 12 patients together with five pairs of parents and subse- quent Sanger sequencing in additional 328 EOEE patients identified two de novo frameshift and one missense mu- tations in SLC35A2 at Xp11.23, respectively. The three patients are all females. X-inactivation analysis of blood leukocyteDNAandmRNAanalysisusinglymphoblastoid cells derived from two patients with a frameshift mutation indicated that only the wild-type SLC35A2 allele was ex- pressed in these cell types, at least in part likely as a con- sequence of skewed X-inactivation. SLC35A2 encodes a UDP-galactose transporter (UGT), which selectively sup- plies UDP-galactose from the cytosol to the Golgi lumen. Transient expression experiments revealed that the mis- Additional Supporting Information may be found in the online version of this article. † These authors contributed equally to this work.