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. 2020 Apr;8(4):e1103.
doi: 10.1002/mgg3.1103. Epub 2020 Feb 7.

Modifier genes in SCN1A-related epilepsy syndromes

Iris M de Lange  1 , Flip Mulder  1 , Ruben van 't Slot  1 , Anja C M Sonsma  1 , Marjan J A van Kempen  1 , Isaac J Nijman  1 , Robert F Ernst  1 , Nine V A M Knoers  1   2 , Eva H Brilstra  1 , Bobby P C Koeleman  1
Affiliations

Modifier genes in SCN1A-related epilepsy syndromes

Iris M de Lange et al. Mol Genet Genomic Med. 2020 Apr.

Abstract

Background: SCN1A is one of the most important epilepsy-related genes, with pathogenic variants leading to a range of phenotypes with varying disease severity. Different modifying factors have been hypothesized to influence SCN1A-related phenotypes. We investigate the presence of rare and more common variants in epilepsy-related genes as potential modifiers of SCN1A-related disease severity.

Methods: 87 patients with SCN1A-related epilepsy were investigated. Whole-exome sequencing was performed by the Beijing Genomics Institute (BGI). Functional variants in 422 genes associated with epilepsy and/or neuronal excitability were investigated. Differences in proportions of variants between the epilepsy genes and four control gene sets were calculated, and compared to the proportions of variants in the same genes in the ExAC database.

Results: Statistically significant excesses of variants in epilepsy genes were observed in the complete cohort and in the combined group of mildly and severely affected patients, particularly for variants with minor allele frequencies of <0.05. Patients with extreme phenotypes showed much greater excesses of epilepsy gene variants than patients with intermediate phenotypes.

Conclusion: Our results indicate that relatively common variants in epilepsy genes, which would not necessarily be classified as pathogenic, may play a large role in modulating SCN1A phenotypes. They may modify the phenotypes of both severely and mildly affected patients. Our results may be a first step toward meaningful testing of modifier gene variants in regular diagnostics for individual patients, to provide a better estimation of disease severity for newly diagnosed patients.

Keywords: SCN1A; Dravet; GEFS+; epilepsy; modifier genes; phenotypic variability.

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Conflict of interest statement

None declared.

Figures

Figure 1
Figure 1
Overrepresentation of variants in epilepsy genes in the cohort. Bars represent the percentage of over‐ or underrepresentation of variants in the different patient groups, based on the ratio of variants found in epilepsy genes and different control groups (ctrl 1, 2, 3, 4 and 1–4), compared to ratios in the ExAC database. (a) Variants in epilepsy genes compared to different control groups; (b) variants in intellectual disability genes compared to different control groups; (c) variants in control group 1 genes compared to control group 3 and 4 (negative control). Results are presented for categories of variants with different allele frequency cut‐offs (<0.01, <0.05, <0.1). Significant values are depicted by asterisks
Figure 2
Figure 2
Distribution of variants in epilepsy genes among different groups of patients. Distribution of variants in epilepsy genes among different groups of patients, depicted for different types of variants (A–E). 1: (type A variants) CADD >20/MAF <0.01; 2: (type B variants) CADD >10/MAF <0.01; 3: (type C variants) all CADD/MAF <0.01; 4: (type D variants) all CADD/MAF <0.05; 5: (type E variants) all CADD/MAF <0.10. Percentages of variants relative to the total number of alleles per group are shown
See this image and copyright information in PMC

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