Novel mutations and phenotypes of epilepsy-associated genes in epileptic encephalopathies

Genes Brain Behav. 2018 Nov;17(8):e12456. doi: 10.1111/gbb.12456. Epub 2018 Jan 26.


Epileptic encephalopathies are severe epilepsy disorders with strong genetic bases. We performed targeted next-generation sequencing (NGS) in 70 patients with epileptic encephalopathies. The likely pathogenicity of variants in candidate genes was evaluated by American College of Medical Genetics and Genomics (ACMG) scoring taken together with the accepted clinical presentation. Thirty-three candidate variants were detected after population filtration and computational prediction. According to ACMG, 21 candidate variants, including 18 de novo variants, were assessed to be pathogenic/likely pathogenic with clinical concordance. Twelve variants were initially assessed as uncertain significance by ACMG, among which 3 were considered causative and 3 others were considered possibly causative after analysis of clinical concordance. In total, 24 variants were identified as putatively causative, among which 19 were novel findings. SCN1A mutations were identified in 50% of patients with Dravet syndrome. TSC1/TSC2 mutations were detected in 66.7% of patients with tuberous sclerosis. STXBP1 mutations were the main findings in patients with West syndrome. Mutations in SCN2A, KCNT1, KCNQ2 and CLCN4 were identified in patients with epileptic infantile with migrating focal seizures; among them, KCNQ2 and CLCN4 were first identified as potential causative genes. Only one CHD2 mutation was detected in patients with Lennox-Gastaut syndrome. This study highlighted the utility of targeted NGS in genetic diagnoses of epileptic encephalopathies and a comprehensive evaluation of the pathogenicity of variants based on ACMG scoring and assessment of clinical concordance. Epileptic encephalopathies differ in genetic causes, and the genotype-phenotype correlations would provide insights into the underlying pathogenic mechanisms.

Keywords: ACMG scoring; clinical phenotype; epileptic encephalopathies; pathogenicity of mutations; targeted next-generation sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Chloride Channels / genetics
  • Epilepsies, Myoclonic / genetics
  • Epilepsy / genetics
  • Epileptic Syndromes / genetics*
  • Female
  • Genetic Association Studies
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Infant
  • KCNQ2 Potassium Channel / genetics
  • Male
  • Mutation
  • NAV1.1 Voltage-Gated Sodium Channel / genetics
  • NAV1.2 Voltage-Gated Sodium Channel / genetics
  • Nerve Tissue Proteins / genetics
  • Phenotype
  • Potassium Channels / genetics
  • Potassium Channels, Sodium-Activated
  • Spasms, Infantile / genetics*
  • Young Adult


  • CLCN4 protein, human
  • Chloride Channels
  • KCNQ2 Potassium Channel
  • KCNQ2 protein, human
  • KCNT1 protein, human
  • NAV1.1 Voltage-Gated Sodium Channel
  • NAV1.2 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins
  • Potassium Channels
  • Potassium Channels, Sodium-Activated
  • SCN1A protein, human
  • SCN2A protein, human