SLC 6A1variants identified in epilepsy patients reduce γ‐aminobutyric acid transport

Summary Previous reports have identifiedSLC6A1variants in patients with generalized epilepsies, such as myoclonic‐atonic epilepsy and childhood absence epilepsy. However, to date, none of the identifiedSLC6A1variants has been functionally tested for an effect onGAT‐1 transporter activity. The purpose of this study was to determine the incidence ofSLC6A1variants in 460 unselected epilepsy patients and to evaluate the impact of the identified variants on γ‐aminobutyric acid (GABA)transport. Targeted resequencing was used to screen 460 unselected epilepsy patients for variants inSLC6A1. Five missense variants, one in‐frame deletion, one nonsense variant, and one intronic splice‐site variant were identified, representing a 1.7% diagnostic yield. Using a [3H]‐GABAtransport assay, the seven identified exonic variants were found to reduceGABAtransport activity. A minigene splicing assay revealed that the splice‐site variant disrupted canonical splicing of exon 9 in themRNAtranscript, leading to premature protein truncation. These findings demonstrate thatSLC6A1is an important contributor to childhood epilepsy and that reducedGAT‐1 function is a common consequence of epilepsy‐causingSLC6A1variants.