Diagnostic yield of genetic testing in epileptic encephalopathy in childhood

Epilepsia. 2015 May;56(5):707-16. doi: 10.1111/epi.12954. Epub 2015 Mar 25.


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.

Significance: 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.

Keywords: Chromosomal; Epilepsy; Genetics; Metabolic disorders; Molecular genetics.

MeSH terms

  • Adolescent
  • Cadherins
  • Child
  • Child, Preschool
  • Cognition Disorders / complications
  • Cognition Disorders / genetics
  • Cohort Studies
  • Developmental Disabilities / complications
  • Developmental Disabilities / genetics
  • Female
  • Genetic Predisposition to Disease*
  • Humans
  • Infant
  • KCNQ2 Potassium Channel
  • Male
  • Munc18 Proteins
  • Mutation / genetics*
  • NAV1.2 Voltage-Gated Sodium Channel
  • Protocadherins
  • Sodium-Hydrogen Exchangers
  • Spasms, Infantile / complications
  • Spasms, Infantile / diagnosis*
  • Spasms, Infantile / genetics*


  • Cadherins
  • KCNQ2 Potassium Channel
  • Munc18 Proteins
  • NAV1.2 Voltage-Gated Sodium Channel
  • PCDH19 protein, human
  • Protocadherins
  • SLC9A2 protein, human
  • STXBP1 protein, human
  • Sodium-Hydrogen Exchangers