SCN1A variants from bench to bedside—improved clinical prediction from functional characterization

Abstract

Variants in the SCN1A gene are associated with a wide range of disorders including genetic epilepsy with febrile seizures plus (GEFS+), familial hemiplegic migraine (FHM), and the severe childhood epilepsy Dravet syndrome (DS). Predicting disease outcomes based on variant type remains challenging. Despite thousands of SCN1A variants being reported, only a minority has been functionally assessed.We review the functional SCN1A work performed to date, critically appraise electrophysiological measurements, compare this to in silico predictions, and relate our findings to the clinical phenotype.Our results show, regardless of the underlying phenotype, that conventional in silico software correctly predicted benign from pathogenic variants in nearly 90%, however was unable to differentiate within the disease spectrum (DS vs. GEFS+ vs. FHM). In contrast, patch-clamp data from mammalian expression systems revealed functional differences among missense variants allowing discrimination between disease severities. Those presenting with milder phenotypes retained a degree of channel function measured as residual whole-cell current, whereas those without any wholecell current were often associated with DS (p = .024).These findings demonstrate that electrophysiological data from mammalian expression systems can serve as useful disease biomarker when evaluating SCN1A variants, particularly in view of new and emerging treatment options in DS. K E Y W O R D SDravet syndrome, electrophysiology, familial hemiplegic migraine, functional testing, GEFS+, patch-clamp, SCN1A *Andreas Brunklaus and Stephanie Schorge contributed equally to this study.

Roles for Countercharge in the Voltage Sensor Domain of Ion Channels

“…Noteworthy on this list are the prevalence of SCN1A mutations identified in genetic screening of patients with intractable epilepsy syndromes. These countercharge mutations have yet to be functionally characterized in heterologous expression (Brunklaus et al, 2020). However, several countercharge mutations identified in cardiac arrhythmia or skeletal muscle syndromes have been characterized, and are described here.…”

Epilepsy Syndromes in the First Year of Life and Usefulness of Genetic Testing for Precision Therapy

“…Treatment of epilepsy remains largely empirical and is often a trial and error rather than a targeted treatment approach ( Figure 2 ). Early genetic testing lays the foundation for a precision diagnosis and thereby precision therapy, but it needs to be backed up by functional testing to provide pathogenicity and to explore the underlying functional effect of a given variant [ 81 ] ( Figure 2 ).…”

Sodium channel epilepsies and neurodevelopmental disorders: from disease mechanisms to clinical application

“…SCN variant position across the gene can further inform potential pathogenicity as most missense variants are clustered in highly conserved areas essential for function, such as the voltage sensor and pore regions 9,48 . Whereas LoF SCN1A missense variants are found in both regions, 49 SCN2/8A variants located in the pore region tend to be LoF and result in NDDs, while variants in the S4 region can be associated with GoF, mixed, or LoF effects 32 . Certain variant locations could, therefore, be used as a surrogate for function and might offer clues regarding medication choice 50 .…”