2. Academic Validation
  3. De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

  • Am J Hum Genet. 2017 Aug 3;101(2):300-310. doi: 10.1016/j.ajhg.2017.07.004.
Ilaria Guella 1,  Marna B McKenzie 1,  Daniel M Evans 1,  Sarah E Buerki 2,  Eric B Toyota 3,  Margot I Van Allen 4,  Epilepsy Genomics Study,  Mohnish Suri 5,  Frances Elmslie 6,  Deciphering Developmental Disorders Study,  Marleen E H Simon 7,  Koen L I van Gassen 7,  Delphine Héron 8,  Boris Keren 8,  Caroline Nava 8,  Mary B Connolly 3,  Michelle Demos 9,  Matthew J Farrer 10
Affiliations

Affiliations

  • 1 Centre for Applied Neurogenetics, University of British Columbia, Vancouver, BC V5R 6H8, Canada.
  • 2 Department of Neuropediatrics, Development, and Rehabilitation, University Children's Hospital, Inselspital, 3010 Berne, Switzerland.
  • 3 Division of Neurology, Department of Pediatrics, University of British Columbia and BC Children's Hospital, Vancouver, BC V6H 3V4, Canada.
  • 4 Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
  • 5 Regional Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham NG5 1PB, UK.
  • 6 South West Thames Regional Genetics Service, St. George's University Hospitals NHS Foundation Trust, London SW17 0QT, UK.
  • 7 Department of Medical Genetics, University Medical Centre Utrecht, 3508 AB Utrecht, the Netherlands.
  • 8 Département de Génétique et Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, Paris 75651, France.
  • 9 Division of Neurology, Department of Pediatrics, University of British Columbia and BC Children's Hospital, Vancouver, BC V6H 3V4, Canada. Electronic address: [email protected].
  • 10 Centre for Applied Neurogenetics, University of British Columbia, Vancouver, BC V5R 6H8, Canada. Electronic address: [email protected].
PMID: 28777935 DOI: 10.1016/j.ajhg.2017.07.004
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.

Keywords

SLC1A2; YWHAG; de novo variants; epileptic encephalopathy; whole-exome sequencing.

Figures