Abstracts

Rationale: Variation in ion channel genes is the most common cause of human epilepsy. Specifically, disease-causing variants in voltage-gated sodium channels (SCN-related disorders) constitute a large proportion of genetic epilepsies and neurodevelopmental disorders. While the nomenclature for genotype and phenotype is well established for ion channel genes, there is a need for a standardized assessment of functional results complicated by heterogeneous documentation across the literature. Functional analyses are increasingly performed at large-scale, necessitating a common format to map functional results and integrate these across distinct electrophysiological studies.

Methods: We developed Functional Electrophysiology Nomenclature for Ion Channels (FENICS), a controlled dictionary to map functional concepts and bin these parameters into various levels of severity. FENICS contains 120 distinct concepts compatible with ClinVar and the Variation Ontology (VariO), a controlled dictionary for the standardized, systematic description of effects, consequences and mechanisms of genetic variations. We assessed the utility of FENICS, translating 148 functional experiments of disease-causing variants in SCN-related disorders (SCN1A n=50, SCN2A n=51, SCN3A n=17, SCN8A n=30) to 912 FENICS terms.

Results: Performing automated reasoning resulting in 4065 inferred annotations of electrophysiological results (FENICS terms), we identify significant heterogeneity of gain-of-function effects in the SCNs, suggesting that hyperpolarizing shifts of voltage dependence of activation, depolarizing shifts of voltage dependence of fast inactivation, increased persistent currents, and accelerated recovery from fast inactivation contribute equally to gain-of-function mechanisms for variants which have been analyzed functionally. In contrast, loss-of-function effects in the SCNs are primarily driven by changes in peak current. By mapping FENICS terms across the SCN Na_v transmembrane domains, decrease or absence of peak current are associated with variants in domains I and II and various gain-of-function parameters (e.g. “Increase in persistent current,” “Impairment or slowing in fast inactivation) show associations with variants in domains III and IV. Comparing functional effects mapped to FENICS terms in paralogous positions across the various sodium channel genes using a formal similarity analysis, we show that functional effects of disease-causing variants in paralogous positions genes are not more similar than expected by chance, limiting the ability to infer functional effects across genes.

Conclusions: Our study maps electrophysiological results in epilepsy-related sodium channelopathies to a standardized dictionary that explores functional effects beyond a binary classification into gain- and loss-of-function. This approach allows for data harmonization and systematic analysis, facilitating the description and identification of potentially treatable biophysical abnormalities for precision medicine approaches.

Funding: Please list any funding that was received in support of this abstract.: The Children's Hospital of Philadelphia, NINDS, The Hartwell Foundation.