A 2020 View on the Genetics of Developmental and Epileptic Encephalopathies

Hannah C. Happ, Gemma L. Carvill*

*Corresponding author for this work

Research output: Contribution to journalReview article

Abstract

Developmental and epileptic encephalopathies (DEEs) can be primarily attributed to genetic causes. The genetic landscape of DEEs has been largely shaped by the rise of high-throughput sequencing, which led to the discovery of new DEE-associated genes and helped identify de novo pathogenic variants. We discuss briefly the contribution of de novo variants to DEE and also focus on alternative inheritance models that contribute to DEE. First, autosomal recessive inheritance in outbred populations may have a larger contribution than previously appreciated, accounting for up to 13% of DEEs. A small subset of genes that typically harbor de novo variants have been associated with recessive inheritance, and often these individuals have more severe clinical presentations. Additionally, pathogenic variants in X-linked genes have been identified in both affected males and females, possibly due to a lack of X-chromosome inactivation skewing. Collectively, exome sequencing has resulted in a molecular diagnosis for many individuals with DEE, but this still leaves many cases unsolved. Multiple factors contribute to the missing etiology, including nonexonic variants, mosaicism, epigenetics, and oligogenic inheritance. Here, we focus on the first 2 factors. We discuss the promises and challenges of genome sequencing, which allows for a more comprehensive analysis of the genome, including interpretation of structural and noncoding variants and also yields a high number of de novo variants for interpretation. We also consider the contribution of genetic mosaicism, both what it means for a molecular diagnosis in mosaic individuals and the important implications for genetic counseling.

Original languageEnglish (US)
Pages (from-to)90-96
Number of pages7
JournalEpilepsy Currents
Volume20
Issue number2
DOIs
StatePublished - Mar 1 2020

Keywords

  • X-linked
  • autosomal recessive
  • de novo
  • developmental and epileptic encephalopathy
  • genetics

ASJC Scopus subject areas

  • Clinical Neurology

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