The ClinGen Epilepsy Gene Curation Expert Panel—Bridging the divide between clinical domain knowledge and formal gene curation criteria

Ingo Helbig, Erin Rooney Riggs, Carrie Anne Barry, Karl Martin Klein, David Dyment, Courtney Thaxton, Bekim Sadikovic, Tristan T. Sands, Jacy L. Wagnon, Khalida Liaquat, Maria Roberta Cilio, Ghayda Mirzaa, Kristen Park, Erika Axeen, Elizabeth Butler, Tanya M. Bardakjian, Pasquale Striano, Annapurna Poduri, Rebecca K. Siegert, Andrew R. GrantKatherine L. Helbig, Heather C. Mefford

Research output: Contribution to journalArticle

Abstract

The field of epilepsy genetics is advancing rapidly and epilepsy is emerging as a frequent indication for diagnostic genetic testing. Within the larger ClinGen framework, the ClinGen Epilepsy Gene Curation Expert Panel is tasked with connecting two increasingly separate fields: the domain of traditional clinical epileptology, with its own established language and classification criteria, and the rapidly evolving area of diagnostic genetic testing that adheres to formal criteria for gene and variant curation. We identify critical components unique to the epilepsy gene curation effort, including: (a) precise phenotype definitions within existing disease and phenotype ontologies; (b) consideration of when epilepsy should be curated as a distinct disease entity; (c) strategies for gene selection; and (d) emerging rules for evaluating functional models for seizure disorders. Given that de novo variants play a prominent role in many of the epilepsies, sufficient genetic evidence is often awarded early in the curation process. Therefore, the emphasis of gene curation is frequently shifted toward an iterative precuration process to better capture phenotypic associations. We demonstrate that within the spectrum of neurodevelopmental disorders, gene curation for epilepsy-associated genes is feasible and suggest epilepsy-specific conventions, laying the groundwork for a curation process of all major epilepsy-associated genes.

Original languageEnglish
Pages (from-to)1476-1484
Number of pages9
JournalHuman Mutation
Volume39
Issue number11
DOIs
Publication statusPublished - Nov 1 2018

Keywords

  • ClinGen/Clinical Genome Resource
  • clinical validity
  • epilepsy
  • epileptic encephalopathy
  • gene–disease association

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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