Clinical data for individuals from families with SLC32A1 variants

Objective: To identify the causative gene in a large unsolved family with genetic epilepsy with febrile seizures plus (GEFS+), we sequenced the genomes of family members, and then determined the contribution of the identified gene to the pathogenicity of epilepsies by examining sequencing data from 2772 additional patients.

Methods: We performed whole genome sequencing of three members of a GEFS+ family. Subsequently, whole exome sequencing (ES) data from 1165 epilepsy patients from the Epi4K dataset and 1329 Australian epilepsy patients from the Epi25 dataset was interrogated. Targeted resequencing was performed on 278 patients with FS or GEFS+ phenotypes. Variants were validated and familial segregation examined by Sanger sequencing.

Results: Eight previously unreported missense variants were identified in SLC32A1, coding for the vesicular inhibitory amino acid co-transporter VGAT. Two variants co- segregated with the phenotype in two large GEFS+ families containing eight and ten affected individuals, respectively. Six further variants were identified in smaller families with GEFS+ or idiopathic generalized epilepsy (IGE).

Conclusions: Missense variants in SLC32A1 cause GEFS+ and IGE. These variants are predicted to alter GABA transport into synaptic vesicles, leading to altered neuronal inhibition. Examination of further epilepsy cohorts will determine the full genotype-phenotype spectrum associated with SLC32A1 variants.