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Title: Association of SLC32A1 Missense Variants With Genetic Epilepsy With Febrile Seizures Plus.
Austin Authors: Heron, Sarah E;Regan, Brigid M;Harris, Rebekah V;Gardner, Alison E;Coleman, Matthew J;Bennett, Mark F ;Grinton, Bronwyn E;Helbig, Katherine L;Sperling, Michael R;Haut, Sheryl;Geller, Eric B;Widdess-Walsh, Peter;Pelekanos, James T;Bahlo, Melanie;Petrovski, Slavé;Heinzen, Erin L;Hildebrand, Michael S ;Corbett, Mark A;Scheffer, Ingrid E ;Gécz, Jozef;Berkovic, Samuel F 
Affiliation: Murdoch Children's Research Institute, Parkville
Department of Paediatrics, Royal Children's Hospital, University of Melbourne
Healthy Mothers, Babies and Children, South Australian Health and Medical Research Institute, Adelaide, Australia
Florey Institute of Neuroscience and Mental Health, Melbourne
Adelaide Medical School, Faculty of Health and Medical Sciences, and Robinson Research Institute, The University of Adelaide, Adelaide, Australia
Institute of Neurology and Neurosurgery at Saint Barnabas, Livingston, NJ
Department of Neurology, Beaumont Hospital, Dublin, Ireland
Royal Brisbane and Women's Hospital, Brisbane, Australia
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
Institute for Genomic Medicine, Columbia University Medical Center, New York, NY
Epilepsy Research Centre
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
Department of Medical Biology, University of Melbourne, Parkville, Australia
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA
Department of Neurology, Thomas Jefferson University, Philadelphia, PA
Department of Neurology, Montefiore Medical Center, Albert Einstein College of Medicine, New York, NY
Issue Date: 4-May-2021 2021-05-04
Publication information: Neurology 2021; 96(18): e2251-e2260
Abstract: 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. 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. 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). 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.
DOI: 10.1212/WNL.0000000000011855
ORCID: 0000-0001-8759-6748
PubMed URL: 34038384
Type: Journal Article
Appears in Collections:Journal articles

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