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.

Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy

“…In our study, panel design originated in 2010, when multiple candidate genes for rare diseases were nominated without sufficient statistical evidence and could not be confirmed in a clinical setting 39 . This was also described specifically for epilepsy genetics 4,16 .…”

“…However, high heterogeneity of epilepsy gene panel content has been observed 4,15 . This is likely due to the dramatically growing number of genes associated with epilepsy and diverse integration in the established panels, often without robust statistical evidence 4,16 . To increase yield in diagnostic sequencing panels, it is essential considering genes with proven disease association as well as a reasonable frequency of pathogenic variants among affected individuals.…”

The Genomics Research and Innovation Network: creating an interoperable, federated, genomics learning system

“…The GRIN epilepsy pilot investigators went on to lead international efforts for harmonization of gene curation criteria with respect to phenotypic information and the expansion of common phenotypic formats such as the Monarch ontology for common presentations of neurodevelopmental disorders. 31 Finally, the GRIN epilepsy pilot study contributed to the first gene discovery in neurodevelopmental disorders based on harmonized and standardized phenotypic information, identifying de novo variants in AP2M1 through a phenotypic similarity analysis based on Human Phenotype Ontology (HPO) terms across the entire GRIN epilepsy cohort and further cohorts. 32 The goal of the short stature pilot project was to identify specific rare subphenotypes of short stature based on clinical characteristics that are readily identifiable as discrete data elements within the EHR.…”

Calcium Channel Dysfunction in Epilepsy: Gain of CACNA1E

“…This discovery is being rapidly facilitated by the increased numbers of patients undergoing genetic testing, particularly within the clinical setting. Indeed, many of the patients identified in the Helbig study were identified through clinical 11 , GGE (complex) 12 Y Gain of function 11 Ca v 3.2 CACNA1H Epilepsy (disputed) 13,14 ? Ca v 3.3 CACNA1I Schizophrenia (candidate) 15 N Abbreviations: AD, autosomal dominant; AR, autosomal recessive; DEE, developmental and epileptic encephalopathy; GGE, genetic generalized epilepsy; ID, intellectual disability; N, no; XLR, X-linked recessive; Y, yes.…”