Modifier genes in SCN1A‐related epilepsy syndromes

Iris M De Lange,Isaac J Nijman,Marjan J A Van Kempen,Eva H Brilstra,Robert F Ernst,Anja C M Sonsma,Flip Mulder,Nine V A M Knoers,Bobby P C Koeleman,Ruben Van 'T Slot

doi:10.1002/mgg3.1103

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.Methods87 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.ResultsStatistically 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.ConclusionOur 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.

Highlights

INTRODUCTION ANDPHYSIOLOGICAL (METABOLIC) BACKGROUND31P MRS studies of skeletal muscle were among the first reported MRS studies of a mammalian organ in situ, and in four decades at least 500 such studies of human muscle have been published, more than of any other organ.[1]
We summarise the metabolic information that can be quantitatively assessed with 31P MRS, either measured directly or derived by calculations that depend on particular metabolic models, and we give advice on potential problems of interpretation
Skeletal muscle 31P MR spectroscopy can provide insights, not otherwise available non-invasively, into the regulation and pathophysiology of what may be summarised as cellular energy metabolism or ‘bioenergetics’: the production and use of Adenosine triphosphate (ATP)

Summary

Introduction

INTRODUCTION ANDPHYSIOLOGICAL (METABOLIC) BACKGROUND31P MRS studies of skeletal muscle were among the first reported MRS studies of a mammalian organ in situ, and in four decades at least 500 such studies of human muscle have been published, more than of any other organ.[1].

Results

Conclusion