Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy

Genet Med. 2016 Sep;18(9):898-905. doi: 10.1038/gim.2015.186. Epub 2016 Jan 21.


Purpose: To assess the yield of diagnostic exome sequencing (DES) and to characterize the molecular findings in characterized and novel disease genes in patients with epilepsy.

Methods: In an unselected sample of 1,131 patients referred for DES, overall results were compared between patients with and without epilepsy. DES results were examined based on age of onset and epilepsy diagnosis.

Results: Positive/likely positive results were identified in 112/293 (38.2%) epilepsy patients compared with 210/732 (28.7%) patients without epilepsy (P = 0.004). The diagnostic yield in characterized disease genes among patients with epilepsy was 33.4% (105/314). KCNQ2, MECP2, FOXG1, IQSEC2, KMT2A, and STXBP1 were most commonly affected by de novo alterations. Patients with epileptic encephalopathies had the highest rate of positive findings (43.4%). A likely positive novel genetic etiology was proposed in 14/200 (7%) patients with epilepsy; this frequency was highest in patients with epileptic encephalopathies (17%). Three genes (COQ4, DNM1, and PURA) were initially reported as likely positive novel disease genes and were subsequently corroborated in independent peer-reviewed publications.

Conclusion: DES with analysis and interpretation of both characterized and novel genetic etiologies is a useful diagnostic tool in epilepsy, particularly in severe early-onset epilepsy. The reporting on novel genetic etiologies may further increase the diagnostic yield.Genet Med 18 9, 898-905.

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • DNA-Binding Proteins / genetics*
  • Dynamins
  • Epilepsy / diagnosis*
  • Epilepsy / genetics
  • Epilepsy / physiopathology
  • Exome Sequencing / methods
  • Female
  • GTP Phosphohydrolases / genetics*
  • Genetic Predisposition to Disease
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Microtubule-Associated Proteins / genetics*
  • Mitochondrial Proteins / genetics*
  • Pathology, Molecular*
  • Transcription Factors / genetics*


  • COQ4 protein, human
  • DNA-Binding Proteins
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • PURA protein, human
  • Transcription Factors
  • GTP Phosphohydrolases
  • DNM1L protein, human
  • Dynamins