De Novo Mutations in YWHAG Cause Early-Onset Epilepsy - Sorbonne Université Access content directly
Journal Articles American Journal of Human Genetics Year : 2017

De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

Sarah Buerki
  • Function : Author
Shelin Adam
  • Function : Author
Cyrus Boelman
  • Function : Author
Corneliu Bolbocean
  • Function : Author
Tara Candido
  • Function : Author
Patrice Eydoux
  • Function : Author
Gabriella Horvath
  • Function : Author
Linda Huh
  • Function : Author
Tanya Nelson
  • Function : Author
Graham Sinclair
  • Function : Author
Clara van Karnebeek
  • Function : Author
Suzanne Vercauteren
  • Function : Author

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 14-3-3γ) (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 = 1) and YWHAG (n = 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.

Dates and versions

hal-04558940 , version 1 (25-04-2024)

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Ilaria Guella, Marna Mckenzie, Daniel Evans, Sarah Buerki, Eric Toyota, et al.. De Novo Mutations in YWHAG Cause Early-Onset Epilepsy. American Journal of Human Genetics, 2017, 101 (2), pp.300-310. ⟨10.1016/j.ajhg.2017.07.004⟩. ⟨hal-04558940⟩
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