2025/10/23 by Peter Müller‐Wöhrstein, Holger Lerche, Christian M. Boßelmann · 2 voices
Biochemistry, Genetics and Molecular Biology · Medicine · #Genetics and Neurodevelopmental Disorders #Epilepsy research and treatment #Genomics and Rare Diseases
paper · pdf · doi:10.1002/epi4.70154
openalex created_date 2025/10/23 · openalex publication_date 2025/10/23 · openalex updated_date 2026/08/01
Variant interpretation has become a key challenge, as sequencing costs continue to decrease and countries such as the United Kingdom implement genome sequencing of every newborn child.1 Specifically for ion channel disorders, variant effects on biophysical function are critical to guide clinical management.2 Here, Takahashi and colleagues used an in silico tool by Heyne et al.3 and evidence from paralog variants to assess the likely functional impact of SCN1A variants in individuals with Dravet syndrome (DS), of which five variants were presumed to result in gain-of-function (GOF) or mixed effects.4 Evaluating the likely functional effect of ion channel variants is difficult. Evidence from paralog variants, especially those with other amino acid substitutions, should be considered carefully and is more accurate if the position is conserved and the phenotype aligns.5, 6 Even if experimental evidence is available, expression in neurons may be required to fully understand function.7-9 We have independently assessed the electrophysiological evidence from paralog variants in the literature. Further, for all variants presented as GOF or mixed by this study, our own tool (SCION) predicts loss-of-function (LOF) instead.10 Taken together with the available clinical information, we believe that 2/5 variants have predominantly LOF effects and 3/5 variants are unclear (Table 1). We believe that this example highlights how challenging variant assessment can be, especially when evidence is incomplete or conflicting. Thus, the community may need to follow similar efforts by the ACMG to establish semi-quantitative evidence frameworks that integrate clinical features (e.g., age at seizure onset, seizure types at onset, presence of febrile seizures), paralog variants, and in silico predictions.11 Ultimately, direct experimental evidence from in vitro electrophysiology remains the gold standard—but this is not available for routine clinical practice. These epilepsy-specific challenges in variant interpretation underline the importance of “variant management conferences” (VMC), as spearheaded by EpiCARE (European Reference Network for Rare and Complex Epilepsies). DS remains an electroclinical diagnosis since its initial description, which may be supported by the detection of a pathogenic SCN1A variant.12 However, we would like to advocate that DS should specifically be reserved for SCN1A variants with (predominantly) LOF effects. Precise disease definitions are becoming increasingly relevant as they define inclusion criteria for natural history studies and clinical trials with antisense oligonucleotides (e.g., MONARCH) or artificial promoters (e.g., ENDEAVOR). If a patient with SCN1A-GOF were to undergo any of these precision treatments, they may not benefit, or their condition may deteriorate. Conversely, even some individuals with SCN1A-LOF may benefit from sodium channel blockers such as lamotrigine or cenobamate, as these drugs also target calcium channels or the predominantly NaV1.6-conducted persistent current.13, 14 Instead, individuals with SCN1A-GOF variants suffer from developmental and epileptic encephalopathies (DEEs) that are clinically distinct from DS, including early-infantile DEE (EIDEE) and neonatal DEE with movement disorder and arthrogryposis (NDEEMA).15 We are not aware that SCN1A-GOF variants can cause a classical DS phenotype. In summary, we encourage epileptologists to reserve the diagnosis of DS for individuals with SCN1A-LOF variants and promote participation in institutional or international VMCs to tailor precision medicine. This work was supported by the EKFS college PRECISE.net, the rare disease network Treat-ION (BMBF, 01GM2210A), and the Research Unit FOR-2715 (DFG, LE1030/16-2 & LE1030/23-1). CB is supported by the MINT-Clinician Scientist program of the Medical Faculty Tübingen (DFG, 493665037). None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.