title: Diagnostic yield of genetic testing in epileptic encephalopathy in childhood.
abstract: OBJECTIVE
  Epilepsy is a common neurologic disorder of childhood. To determine the genetic diagnostic yield in epileptic encephalopathy, we performed a retrospective cohort study in a single epilepsy genetics clinic.
  
  
  METHODS
  We included all patients with intractable epilepsy, global developmental delay, and cognitive dysfunction seen between January 2012 and June 2014 in the Epilepsy Genetics Clinic. Electronic patient charts were reviewed for clinical features, neuroimaging, biochemical investigations, and molecular genetic investigations including targeted next-generation sequencing of epileptic encephalopathy genes.
  
  
  RESULTS
  Genetic causes were identified in 28% of the 110 patients: 7% had inherited metabolic disorders including pyridoxine dependent epilepsy caused by ALDH7A1 mutation, Menkes disease, pyridox(am)ine-5-phosphate oxidase deficiency, cobalamin G deficiency, methylenetetrahydrofolate reductase deficiency, glucose transporter 1 deficiency, glycine encephalopathy, and pyruvate dehydrogenase complex deficiency; 21% had other genetic causes including genetic syndromes, pathogenic copy number variants on array comparative genomic hybridization, and epileptic encephalopathy related to mutations in the SCN1A, SCN2A, SCN8A, KCNQ2, STXBP1, PCDH19, and SLC9A6 genes. Forty-five percent of patients obtained a genetic diagnosis by targeted next-generation sequencing epileptic encephalopathy panels. It is notable that 4.5% of patients had a treatable inherited metabolic disease.
  
  
  CONCLUSIONS
  To the best of our knowledge, this is the first study to combine inherited metabolic disorders and other genetic causes of epileptic encephalopathy. Targeted next-generation sequencing panels increased the genetic diagnostic yield from <10% to >25% in patients with epileptic encephalopathy.
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.|Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Saadet
authors.initials: S
authors.lastname: Mercimek-Mahmutoglu
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jaina
authors.initials: J
authors.lastname: Patel
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Dawn
authors.initials: D
authors.lastname: Cordeiro
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stacy
authors.initials: S
authors.lastname: Hewson
authors.affiliation: Division of Neurology, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Callen
authors.affiliation: Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Donner
authors.affiliation: Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Cecil D
authors.initials: CD
authors.lastname: Hahn
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.|Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Kannu
authors.affiliation: Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jeff
authors.initials: J
authors.lastname: Kobayashi
authors.affiliation: Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.|Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.|University of Toronto Michael Bahen Chair in Epilepsy Research, Toronto, Ontario, Canada.
authors.forename: Berge A
authors.initials: BA
authors.lastname: Minassian
authors.affiliation: Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mahendranath
authors.initials: M
authors.lastname: Moharir
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Komudi
authors.initials: K
authors.lastname: Siriwardena
authors.affiliation: Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Shelly K
authors.initials: SK
authors.lastname: Weiss
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.|Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
authors.affiliation: Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: O Carter
authors.initials: OC
authors.lastname: Snead
mesh_terms: D000293:Adolescent; D015820:Cadherins; D002648:Child; D002675:Child, Preschool; D003072:Cognition Disorders / Q000150:complications / Q000235:genetics; D015331:Cohort Studies; D002658:Developmental Disabilities / Q000150:complications / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D051658:KCNQ2 Potassium Channel; D008297:Male; D051938:Munc18 Proteins; D009154:Mutation / Q000235:genetics*; D062551:NAV1.2 Voltage-Gated Sodium Channel; D000091363:Protocadherins; D017923:Sodium-Hydrogen Exchangers; D013036:Spasms, Infantile / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D015820:Cadherins; D051658:KCNQ2 Potassium Channel; D051938:Munc18 Proteins; D062551:NAV1.2 Voltage-Gated Sodium Channel; C438605:PCDH19 protein, human; D000091363:Protocadherins; C081517:SLC9A2 protein, human; C497937:STXBP1 protein, human; D017923:Sodium-Hydrogen Exchangers
keywords: Chromosomal; Epilepsy; Genetics; Metabolic disorders; Molecular genetics