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

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.

Keywords: ClinGen/Clinical Genome Resource; clinical validity; epilepsy; epileptic encephalopathy; gene-disease association.

Figure 1.

Gene selection and precuration process within the ClinGen Epilepsy Gene Curation Expert Panel. Starting with a broad candidate list of genes compiled from genes available on commercial gene panel (n=2702) the possible candidate genes are narrowed down and supplemented by genes with diagnostic relevance, genes with statistical evidence and genes suggested by expert opinion. This selection process provides a narrower list of candidate genes, including 123 candidate genes as of April 2018. This list of candidates is dynamic and may integrate further genes once evidence for these genes arises. From the 123 candidate genes, 29 genes were selected for the pilot phase of the ClinGen Epilepsy Gene Curation Expert Panel for an iterative precuration process, during which the phenotypic spectrum of genes was reviewed. Genes with primary phenotypes reviewed in other working groups or expert panels were excluded and genes with dual phenotypes were selected to be curated for a primary epilepsy phenotype. These genes are then carried forward for a standard ClinGen gene curation process. During the pilot phase, a small selection of genes was chosen to refine rules for genetic and experimental evidence and selection and, if necessary, modification of MONDO terms.

Figure 2.

Differences between then MONDO ontology used in the ClinGen gene curation process and the International League Against Epilepsy (ILAE) classification, using the example of Dravet Syndrome (MONDO_0011794. Within the MONDO classification, the term Dravet Syndrome has both parent terms and child terms. The parent terms are different clinical and genetic concepts that comprise Dravet Syndrome as an entity, such as “Infantile Epilepsy Syndrome” (MONDO_0020071) or “Infancy electroclinical syndrome” (MONDO_000413). The term Dravet Syndrome is synonymous with Early Infantile Epileptic Encephalopathy (EIEE), type 6 (SCN1A) and has two child terms, EIEE4 (STXBP1) and EIEE19 (GABRA1). Within the ILAE classification, seizure types, epilepsy types, and epilepsy syndromes are classified on three levels, defining seizures types (generalized and occasional focal seizures in Dravet Syndrome), epilepsy types (generalized epilepsy), and epilepsy syndrome. The ILAE classification does not formally classify epilepsy syndromes by diagnostic criteria, but states that electroclinical syndromes are clusters of features incorporating seizure types, EEG and imaging features that tend to occur together, referring to the ILAE educational resource epilepsydiagnosis.org that provides examples, diagnostic parameters, review videos of seizure types and the EEG features of many established syndromes, including Dravet Syndrome. In addition, the ILAE classification suggests to provide an etiology for each level, including a genetic etiology.