Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy

Nat Commun. 2019 Jun 7;10(1):2506. doi: 10.1038/s41467-019-10482-9.


Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10-6) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics
  • Asian People / genetics
  • Case-Control Studies
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • Epilepsies, Myoclonic / genetics
  • Exome Sequencing
  • Genetic Variation*
  • Guanine Nucleotide Exchange Factors / genetics
  • Humans
  • Infant
  • Japan
  • Lennox Gastaut Syndrome / genetics
  • Logistic Models
  • Mutation
  • Neurofibromin 1 / genetics
  • Polymorphism, Single Nucleotide
  • Principal Component Analysis
  • Spasms, Infantile / genetics*
  • TRPM Cation Channels / genetics


  • AP5B1 protein, human
  • ARFGEF1 protein, human
  • Adaptor Proteins, Vesicular Transport
  • Guanine Nucleotide Exchange Factors
  • NF1 protein, human
  • Neurofibromin 1
  • TRPM Cation Channels
  • TRPM5 protein, human
  • DNMT3L protein, human
  • DNA (Cytosine-5-)-Methyltransferases

Supplementary concepts

  • Epileptic Encephalopathy, Early Infantile, 3
  • Infantile Epileptic-Dyskinetic Encephalopathy