Evaluating the pathogenic potential of genes with de novo variants in epileptic encephalopathies

Genet Med. 2019 Jan;21(1):17-27. doi: 10.1038/s41436-018-0011-y. Epub 2018 Jun 12.


Epileptic encephalopathies comprise a group of catastrophic epilepsies with heterogeneous genetic etiology. Although next-generation sequencing techniques can reveal a number of de novo variants in epileptic encephalopathies, evaluating the pathogenicity of these variants can be challenging. Determining the pathogenic potential of genes in epileptic encephalopathies is critical before evaluating the pathogenicity of variants identified in an individual. We reviewed de novo variants in epileptic encephalopathies, including their genotypes and functional consequences. We then evaluated the pathogenic potential of genes, with the following additional considerations: (1) recurrence of variants in unrelated cases, (2) information of previously defined phenotypes, and (3) data from genetic experimental studies. Genes related to epileptic encephalopathy revealed pathogenicity with distinct functional alterations, i.e., either a gain of function or loss of function in the majority; however, several genes warranted further study to confirm their pathogenic potential. Whether a gene was associated with distinct phenotype, the genotype (or functional alteration)--phenotype correlation, and quantitative correlation between genetic impairment and phenotype severity were suggested to be specific evidence in determining the pathogenic role of genes. Data from epileptic encephalopathy-related genes would be helpful in outlining guidelines for evaluating the pathogenic potential of genes in other genetic disorders.

Keywords: de novo variant; epilepsy; epileptic encephalopathy; next generation sequencing; pathogenicity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Genetic Association Studies*
  • Genetic Predisposition to Disease*
  • Genetic Variation / genetics*
  • Genotype
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Mutation
  • Phenotype
  • Spasms, Infantile / genetics*
  • Spasms, Infantile / pathology

Supplementary concepts

  • Infantile Epileptic-Dyskinetic Encephalopathy