De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

Abstract

Massively parallel sequencing has revealed many de novo mutations in the etiology of developmental and epileptic encephalopathies (EEs), highlighting their genetic heterogeneity. Additional candidate genes have been prioritized in silico by their co-expression in the brain. Here, we evaluate rare coding variability in 20 candidates nominated with the use of a reference gene set of 51 established EE-associated genes. Variants within the 20 candidate genes were extracted from exome-sequencing data of 42 subjects with EE and no previous genetic diagnosis. We identified 7 rare non-synonymous variants in 7 of 20 genes and performed Sanger sequence validation in affected probands and parental samples. De novo variants were found only in SLC1A2 (aka EAAT2 or GLT1) (c.244G>A [p.Gly82Arg]) and YWHAG (aka 14-3-3g) (c.394C>T [p.Arg132Cys]), highlighting the potential cause of EE in 5% (2/42) of subjects. Seven additional subjects with de novo variants in SLC1A2 (n ¼ 1) and YWHAG (n ¼ 6) were subsequently identified through online tools. We identified a highly significant enrichment of de novo variants in YWHAG, establishing their role in early-onset epilepsy, and we provide additional support for the prior assignment of SLC1A2. Hence, in silico modeling of brain co-expression is an efficient method for nominating EE-associated genes to further elucidate the disorder's etiology and genotype-phenotype correlations.

Expanding the genotype–phenotype correlation ofde novoheterozygous missense variants inYWHAGas a cause of developmental and epileptic encephalopathy

“…Previous to this, in 2013, Allen et al In the only YWHAG series to-date, Guella et al, 2017 described four patients with de novo variants in YWHAG and suggested it as a cause of early-onset epilepsy, DEE and ID (Guella et al, 2017). In this series, the de novo variants were predicted to impair dimerization and phosphopeptide binding.…”

Region‐specific deletions of the glutamate transporter GLT1 differentially affect seizure activity and neurodegeneration in mice

“…Recent human genetic studies identified 5 heterozygous SLC1A2 (EAAT2/GLT1) mutations in patients and families with either of epileptic encephalopathy, early myoclonic encephalopathy, early-onset epileptic encephalopathy or infantile spasms (Epi4K Consortium, 2013Consortium, , 2016Guella, et al, 2017). All individuals had early-onset multiple seizure types with prominent myoclonic and tonic seizures as well as spasms.…”

“…There are five structurally distinct subtypes of Na 1 -dependent glutamate transporters, GLAST (EAAT1), GLT1 (EAAT2), EAAC1 (EAAT3), EAAT4 and EAAT5. Recent genetic studies in human populations have suggested that de novo mutations in EAAT2 (GLT1) cause early-onset epilepsy with multiple seizure types (Epi4K Consortium, 2013, 2016Guella, et al, 2017). GLT1, which is the most prominently expressed glutamate transporter in the mammalian CNS, plays a key role in the maintenance of extracellular glutamate homeostasis to protect neurons from excitotoxicity (Coulter & Eid, 2012;Takahashi, Foster, & Lin, 2015).…”

The expanding spectrum of movement disorders in genetic epilepsies

“…Motor features including spasticity, ataxia, and choreoathetosis are often present. 84,85 Mutations in YWHAG, encoding a member of the 14-3-3 protein family involved in intracellular signalling, protein trafficking, cell-cycle control, and apoptosis, 78 cause DEE characterized by variable seizure types (focal motor, GTCS, myoclonic, absence), ataxia, and tremor. 78,79 Genes with other cellular functions Biallelic mutations in UBA5, a gene involved in protein posttranslational modification, cause DEE including Ohtahara syndrome, West syndrome, or myoclonic jerks, and axial or peripheral hypotonia.…”