Association of SLC32A1 missense variants with genetic epilepsy with febrile seizures plus

Heron, SE; Regan, BM; Harris, RV; Gardner, AE; Coleman, MJ; Bennett, MF; Grinton, BE; Helbig, KL; Sperling, MR; Haut, S; Geller, EB; Widdess-Walsh, P; Pelekanos, JT; Bahlo, M; Petrovski, S; Heinzen, EL; Hildebrand, MS; Corbett, MA; Scheffer, IE; G&#233;cz, J; Berkovic, SF

Author(s): Heron, SE; Regan, BM; Harris, RV; Gardner, AE; Coleman, MJ; Bennett, MF; Grinton, BE; Helbig, KL; Sperling, MR; Haut, S; Geller, EB; Widdess-Walsh, P; Pelekanos, JT; Bahlo, M; Petrovski, S; Heinzen, EL; Hildebrand, MS; Corbett, MA; Scheffer, IE; Gécz, J; Berkovic, SF;
Details: Publication Year 2021-05-04,Volume 96,Issue #18,Page e2251-e2260
Journal Title: Neurology
Abstract: 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 2,772 additional patients. METHODS: We performed whole genome sequencing of 3 members of a GEFS+ family. Subsequently, whole exome sequencing data from 1,165 patients with epilepsy from the Epi4K dataset and 1,329 Australian patients with epilepsy from the Epi25 dataset were interrogated. Targeted resequencing was performed on 278 patients with febrile seizures 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 cotransporter VGAT. Two variants cosegregated with the phenotype in 2 large GEFS+ families containing 8 and 10 affected individuals, respectively. Six further variants were identified in smaller families with GEFS+ or idiopathic generalized epilepsy (IGE). CONCLUSION: Missense variants in SLC32A1 cause GEFS+ and IGE. These variants are predicted to alter γ-aminobutyric acid (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.
Publisher: American Academy of Neurology
Research Division(s): Population Health And Immunity
PubMed ID: 34038384
Publisher's Version: https://doi.org/10.1212/wnl.0000000000011855
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2021-06-02 01:45:58

Last Modified: 2021-06-02 01:48:20