Review
The unexpected role of copy number variations in juvenile myoclonic epilepsy

https://doi.org/10.1016/j.yebeh.2012.07.005Get rights and content

Abstract

Structural genomic variants or copy number variants (CNVs) comprise submicroscopic deletions and duplications of chromosomal material, including both rearrangements at genomic hotspots as well as duplications and deletions with unique breakpoints. Copy number variants have increasingly been recognized in the Idiopathic/Genetic Generalized Epilepsies (IGE/GGE) including juvenile myoclonic epilepsy (JME). Microdeletions at 15q13.3, 15q11.2, and 16p13.11 are genetic risk factors that can be identified in 3% of patients with IGE including JME. These microdeletions, however, also represent genetic risk factors to a broad range of other neurodevelopmental disorders. Additionally, 6% of patients with GGE carry other, potentially pathogenic structural genomic variants. While family studies largely support the channelopathy concept of the idiopathic epilepsies, the results of studies investigating copy number variations suggest that JME genetically overlaps with a broad range of other neurodevelopmental disorders. In addition, the particular genetic properties of structural genomic variations as rare genetic variants highlight the complexity of the genetic architecture of human disease.

This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?

Highlights

► Recurrent microdeletions are risk factors found in 3% of patients with JME. ► Microdeletions also represent risk factors to other neurological disorders. ► JME genetically overlaps with other neurodevelopmental disorders. ► CNVs highlight the complexity of the genetic architecture of human disease.

Introduction

Human genetic variation can occur on a broad spectrum ranging from single base pair variation to large aneuploidies involving entire chromosomes. However, due to methodological difficulties, genetic variation between both extremes has historically been difficult to assess. Eventually, the advent of array-based genetic technologies, including bacterial artificial chromosome (BAC) arrays, array comparative genomic hybridization (array CGH) and Single Nucleotide Polymorphism (SNP) arrays, made it possible to assess structural genomic variation. Surprisingly, initial genetic studies already identified a wide range of normal structural genomic variation in population studies with up to 5% of the human genome considered to be copy number variants [1] (Fig. 1). By definition, variants exceeding 1 kilobase (1000 base pairs) are considered copy number variations. Even though more recent studies have suggested that initial findings might have been overestimated [2], the amount of structural genetic variation came as a surprise. This was particularly true for the field of epilepsy genetics, which was historically focused on single base pair mutations identified in large families.

Section snippets

Identification of the first CNVs in JME

Even though earlier studies had already described some cases of juvenile myoclonic epilepsy due to structural genomic variations including microdeletions in 22q11.2 [3], the interest in CNVs was only kindled after the first description of the 15q13.3 microdeletions in intellectual disability and epilepsy [4]. As the 15q13.3 microdeletion comprised the CHRNA7 gene, a long-standing epilepsy candidate gene in a candidate region for JME [5], this variant was the first microdeletion to be examined

Microdeletions in epilepsy and rearrangements at genetic hotspots

Following the identification of the 15q13.3 microdeletion, other microdeletions were identified in JME including recurrent variants at 15q11.2 and 16p13.11 [10], [12]. These variants are more frequently identified in unaffected individuals, and the risk conferred by these variants is smaller compared to the 15q13.3 microdeletion. All three variants share a common genetic architecture and represent the so-called “genetic hotspots” [13]. Genetic hotspots arise due to misalignment of segmental

The absence of ion channel genes in JME-related structural genomic variations and shared pathophysiological pathways with other neurodevelopmental disorders

Many existing genetic findings from monogenic families support the channelopathy concept of idiopathic epilepsies [19]. In brief, the concept stipulates that genetic variation in ion channel genes or functional modification of the proteins is the pathophysiological correlate of idiopathic epilepsies including JME. Based on this assumption, many ion channel genes were considered prime candidate genes for JME association studies. Given the focus on ion channel genes, copy number variations were

CNVs as examples of rare variants

Genetic risk factors contributing to human disease can be classified according to their frequency in the population and the risk conferred by the variant, usually expressed as a risk ratio or odds ratio. In the past decades, genetic research has largely focused on the extremes of this spectrum, i.e., vary rare variants with a very high risk including monogenic variants identified in families or de novo through linkage studies or candidate gene studies as well as common genetic variants with a

Outlook on future CNV studies in JME

Structural genomic variations contribute to the pathogenesis of JME, and recurrent variants at 15q13.3, 15q11.2, and 16p13.3 are known and established risk factors present in 3% of patients with JME. However, twice as many patients with JME carry rare structural genomic variations, which are difficult to distinguish from benign variants given the lack of recurrence. With an increasing number of patients with neurodevelopmental disorders genotyped for structural genomic variations either through

Conflict of interest statement

The authors declare that there are no conflicts of interest.

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