Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice

Clin Genet. 2018 May;93(5):1057-1062. doi: 10.1111/cge.13203. Epub 2018 Mar 23.


Although genetic revolution of recent years has vastly expanded a list of genes implicated in epilepsies, complex architecture of epilepsy genetics is still largely unknown, consequently, universally accepted workflows for epilepsy genetic testing in a clinical practice are missing. We present a comprehensive NGS-based diagnostic approach addressing both the clinical and genetic heterogeneity of disorders involving epilepsy or seizures. A bioinformatic panel of 862 epilepsy- or seizure-associated genes was applied to Mendeliome (4813 genes) or whole-exome sequencing data as a first stage, while the second stage included untargeted variant interpretation. Eighty-six consecutive patients with epilepsy or seizures associated with neurodevelopmental disorders and/or congenital malformations were investigated. Of the 86 probands, 42 harbored pathogenic and likely pathogenic variants, giving a diagnostic yield of 49%. Two patients were diagnosed with pathogenic copy number variations and 2 had causative mitochondrial DNA variants. Eleven patients (13%) were diagnosed with diseases with specific treatments. Besides, genomic approach in diagnostics had multiple additional benefits due to mostly non-specific, overlapping, not full-blown phenotypes and abilities to diagnose novel and ultra rare epilepsy-associated diseases. Likely pathogenic variants were identified in SOX5 gene, not previously associated with epilepsy, and UBA5, a recently associated with epilepsy gene.

Keywords: SOX5; UBA5; diagnostic yield; epilepsy genetics; monogenic epilepsies; next-generation sequencing.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Child
  • Child, Preschool
  • DNA Copy Number Variations / genetics
  • Epileptic Syndromes / diagnosis
  • Epileptic Syndromes / genetics*
  • Epileptic Syndromes / pathology
  • Exome / genetics
  • Female
  • Genetic Heterogeneity
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Phenotype
  • SOXD Transcription Factors / genetics*
  • Sequence Analysis, DNA
  • Ubiquitin-Activating Enzymes / genetics*
  • Whole Exome Sequencing*
  • Young Adult


  • SOX5 protein, human
  • SOXD Transcription Factors
  • UBA5 protein, human
  • Ubiquitin-Activating Enzymes