Journal
NEUROLOGY
Volume 96, Issue 18, Pages E2251-E2260Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0000000000011855
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Funding
- National Health and Medical Research Council of Australia [1091593, 1085984, 1102971, 1104831]
- Independent Research Institute Infrastructure Support Scheme
- Victorian State Government Operational Infrastructure Program
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By sequencing genomes of family members, eight previously unreported missense variants in SLC32A1 were identified to cause genetic epilepsy, impacting GABA transport and neuronal inhibition. Further examination of epilepsy cohorts is needed to fully understand the genotype-phenotype spectrum associated with SLC32A1 variants.
ObjectiveTo 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.MethodsWe 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.ResultsEight 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).ConclusionMissense variants in SLC32A1 cause GEFS+ and IGE. These variants are predicted to alter ?-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.
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