Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes

Hum Mutat. 2017 Feb;38(2):216-225. doi: 10.1002/humu.23149. Epub 2016 Dec 9.


Targeted resequencing gene panels are used in the diagnostic setting to identify gene defects in epilepsy. We performed targeted resequencing using a 30-genes panel and a 95-genes panel in 349 patients with drug-resistant epilepsies beginning in the first years of life. We identified 71 pathogenic variants, 42 of which novel, in 30 genes, corresponding to 20.3% of the probands. In 66% of mutation positive patients, epilepsy onset occurred before the age of 6 months. The 95-genes panel allowed a genetic diagnosis in 22 (6.3%) patients that would have otherwise been missed using the 30-gene panel. About 50% of mutations were identified in genes coding for sodium and potassium channel components. SCN2A was the most frequently mutated gene followed by SCN1A, KCNQ2, STXBP1, SCN8A, CDKL5, and MECP2. Twenty-nine mutations were identified in 23 additional genes, most of them recently associated with epilepsy. Our data show that panels targeting about 100 genes represent the best cost-effective diagnostic option in pediatric drug-resistant epilepsies. They enable molecular diagnosis of atypical phenotypes, allowing to broaden phenotype-genotype correlations. Molecular diagnosis might influence patients' management and translate into better and specific treatment recommendations in some conditions.

Keywords: epilepsy; gene panel; mutation; next-generation sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Age of Onset
  • Alleles
  • Anticonvulsants / pharmacology
  • Anticonvulsants / therapeutic use
  • Child
  • Child, Preschool
  • Computational Biology / methods
  • Drug Resistance / genetics*
  • Epilepsy / diagnosis*
  • Epilepsy / drug therapy
  • Epilepsy / genetics*
  • Female
  • Gene Expression Profiling
  • Genetic Association Studies*
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Infant
  • Infant, Newborn
  • Magnetic Resonance Imaging / methods
  • Male
  • Molecular Sequence Annotation
  • Mutation*
  • Phenotype
  • Sequence Analysis, DNA


  • Anticonvulsants