From the Adelaide Medical School, Faculty of Health and Medical Sciences (S.E.H., A.E.G., M.A.C., J.G.), and Robinson Research Institute (J.G.), The University of Adelaide; Epilepsy Research Centre, Department of Medicine (B.M.R., R.V.H., M.C., B.E.G., M.F.B., S.P., M.S.H., I.E.S., S.F.B.), Austin Health, University of Melbourne, Heidelberg; Population Health and Immunity Division (M.F.B., M.B.), The Walter and Eliza Hall Institute of Medical Research; Department of Medical Biology (M.F.B., M.B.), University of Melbourne, Parkville, Australia; Division of Neurology (K.L.H.), Children's Hospital of Philadelphia; Department of Neurology (M.R.S.), Thomas Jefferson University, Philadelphia, PA; Department of Neurology (S.H.), Montefiore Medical Center, Albert Einstein College of Medicine, New York, NY; Institute of Neurology and Neurosurgery at Saint Barnabas (E.B.G.), Livingston, NJ; Department of Neurology (P.W.-W.), Beaumont Hospital, Dublin, Ireland; Royal Brisbane and Women's Hospital (J.T.P.), Brisbane, Australia; Centre for Genomics Research (S.P.), Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK; Institute for Genomic Medicine (E.L.H.), Columbia University Medical Center, New York, NY; Murdoch Children's Research Institute (M.S.H., I.E.S.), Parkville; Department of Paediatrics (I.E.S.), Royal Children's Hospital, University of Melbourne; Florey Institute of Neuroscience and Mental Health (I.E.S.), Melbourne; and Healthy Mothers, Babies and Children (J.G.), South Australian Health and Medical Research Institute, Adelaide, Australia.
Neurology. 2021 May 4;96(18):e2251-e2260. doi: 10.1212/WNL.0000000000011855. Epub 2021 Mar 23.
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 , 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 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 variants.
通过对一个遗传癫痫伴热性惊厥附加症（GEFS+）的大型未解决家系成员进行基因组测序，以确定其致病基因。然后，通过检查来自 2772 名额外癫痫患者的测序数据，确定所鉴定基因对癫痫发病机制的贡献。
对一个 GEFS+家系的 3 名成员进行全基因组测序。随后，对 Epi4K 数据集的 1165 名癫痫患者和 Epi25 数据集的 1329 名澳大利亚癫痫患者的全外显子组测序数据进行了分析。对 278 名有热性惊厥或 GEFS+表型的患者进行了靶向重测序。通过 Sanger 测序对变体进行验证和家系分离分析。
在编码囊泡抑制性氨基酸共转运蛋白 VGAT 的基因中发现了 8 个以前未报道的错义变异。这两个变异在包含 8 名和 10 名受影响个体的 2 个大的 GEFS+家系中与表型共分离。在具有 GEFS+或特发性全面性癫痫（IGE）的较小家系中又发现了 6 个进一步的变异。
编码 VGAT 的基因中的错义变异导致 GEFS+和 IGE。这些变异预计会改变 GABA 进入突触小泡的转运，从而导致神经元抑制的改变。对进一步的癫痫队列进行检查将确定与 变异相关的完整基因型-表型谱。
