Influence of common SCN1A promoter variants on the severity of SCN1A‐related phenotypes

Abstract

Background Pathogenic variants in SCN1A cause variable epilepsy disorders with different disease severities. We here investigate whether common variation in the promoter region of the unaffected SCN1A allele could reduce normal expression, leading to a decreased residual function of Nav1.1, and therefore to more severe clinical outcomes in patients affected by pathogenic SCN1A variants. Methods Five different SCN1A promoter‐haplotypes were functionally assessed in SH‐SY5Y cells using Firefly and Renilla luciferase assays. The SCN1A promoter region was analyzed in a cohort of 143 participants with SCN1A pathogenic variants. Differences in clinical features and outcomes between participants with and without common variants in the SCN1A promoter‐region of their unaffected allele were investigated. Results All non‐wildtype haplotypes showed a significant reduction in luciferase expression, compared to the wildtype promoter‐region (65%–80%, p = 0.039–0.0023). No statistically significant differences in clinical outcomes were observed between patients with and without common promoter variants. However, patients with a wildtype promoter‐haplotype on their unaffected SCN1A allele showed a nonsignificant trend for milder phenotypes. Conclusion The nonsignificant observed trends in our study warrant replication studies in larger cohorts to explore the potential modifying role of these common SCN1A promoter‐haplotypes.

Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A

“…This exon was previously identified based on targeted sequencing of the locus, 33 although it was absent in annotation catalogues until our work in this study. At the current time, there is limited evidence for an association of this exon with disease, 34 although we suspect it remains largely unstudied in a clinical context. Certainly, the biological validity of the exon is underpinned by strong transcriptomics support in multiple data sources and also the fact that it is conserved in mammalian and avian genomes, with brain-specific transcriptomics support in mouse and chicken (not shown).…”

SCN1A IVS5N+5 G>A Polymorphism and Risk of Febrile Seizure and Epilepsy: A Systematic Review and Meta-Analysis

“…This is probably due to the fact that the neuronal membrane excitability is a closely regulated factor and that change in the function of the ion channel can result in the corresponding alternation in other channels (31). Some SNPs in the SCN1A gene have been detected frequently among children with an extremely severe type of epilepsy (32). Among these SNPs, emerging evidence shows that the IVS5N+5 G>A polymorphism plays an important role (18).…”

Deletion of a non-canonical regulatory sequence causes loss of Scn1a expression and epileptic phenotypes in mice

“…Further, genome-wide association studies (GWAS) have implicated non-coding SCN1A DNA variants as contributing to epilepsy risk [33,34], presumably via more subtle perturbation to transcriptional regulation, and non-coding promoter deletions have been found in DS patients [35,36]. A recent study of common variation in the promoter regions of SCN1A found that promoter variant haplotypes reduced luciferase in cells and that such non-coding variants in the functional SCN1A allele may modify DS severity [37]. Based on these findings, it is plausible that pathogenic variation in regulatory regions modulates SCN1A transcription, contributing to epilepsy.…”