Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/131040
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Type: Journal article
Title: Association of SLC32A1 missense variants with genetic epilepsy with febrile seizures plus
Author: Heron, S.E.
Regan, B.M.
Harris, R.V.
Gardner, A.E.
Coleman, M.J.
Bennett, M.F.
Grinton, B.E.
Helbig, K.L.
Sperling, M.R.
Haut, S.
Geller, E.B.
Widdess-Walsh, P.
Pelekanos, J.T.
Bahlo, M.
Petrovski, S.
Heinzen, E.L.
Hildebrand, M.S.
Corbett, M.A.
Scheffer, I.E.
Gecz, J.
et al.
Citation: Neurology, 2021; 96(18):1-10
Publisher: Ovid Technologies
Issue Date: 2021
ISSN: 0028-3878
1526-632X
Statement of
Responsibility: 
Sarah E. Heron, Brigid M. Regan, Rebekah V. Harris, Alison E. Gardner, Matthew J. Coleman, Mark F. Bennett ... et al.
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.
Keywords: Humans
Epilepsy, Generalized
Seizures, Febrile
Pedigree
Mutation, Missense
Female
Male
Vesicular Inhibitory Amino Acid Transport Proteins
Genetic Variation
Genetic Association Studies
Rights: © 2021 American Academy of Neurology.
DOI: 10.1212/wnl.0000000000011855
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