ReviewThe unexpected role of copy number variations in juvenile myoclonic epilepsy
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.
References (26)
- et al.
Juvenile myoclonic epilepsy with photosensitivity in a female with Velocardiofacial syndrome (del(22)(q11.2)) — causal relationship or coincidence?
Seizure
(2009) - et al.
Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes
Am J Hum Genet
(2010) - et al.
Duplication hotspots, rare genomic disorders, and common disease
Curr Opin Genet Dev
(2009) - et al.
Navigating the channels and beyond: unravelling the genetics of the epilepsies
Lancet Neurol
(2008) - et al.
Global variation in copy number in the human genome
Nature
(2006) - et al.
Integrated detection and population-genetic analysis of SNPs and copy number variation
Nat Genet
(2008) - et al.
A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures
Nat Genet
(2008) - et al.
Genetic mapping of a major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q
Hum Mol Genet
(1997) - et al.
Large recurrent microdeletions associated with schizophrenia
Nature
(2008) Rare chromosomal deletions and duplications increase risk of schizophrenia
Nature
(2008)
Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome
J Med Genet
15q13.3 microdeletions increase risk of idiopathic generalized epilepsy
Nat Genet
Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies
Brain
Cited by (16)
Generalized epilepsies
2019, Handbook of Clinical NeurologyCitation Excerpt :This concept is supported, for instance, by the clinical evidence that also SYNGAP1 gene mutations cause an epilepsy phenotype predominantly represented by childhood onset absences with eyelid myoclonia and tonic–clonic seizures in patients with cognitive and behavior impairment (Klitten et al., 2011; Mignot et al., 2016). Structural genomic variants or copy number variants (CNVs) have increasingly been recognized in the IGEs and, combining the results from several studies, it appears that 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 (Helbig et al., 2013). However, these microdeletions also represent genetic risk factors for a broad range of other neurodevelopmental disorders.
Delineating a new critical region for juvenile myoclonic epilepsy at the 22q11.2 chromosome
2013, Epilepsy and BehaviorClarifying the role of the 22q11.2 microdeletion in juvenile myoclonic epilepsy
2013, Epilepsy and BehaviorIdiopathic Generalized Epilepsies
2019, The Causes of Epilepsy: Common and Uncommon Causes in Adults and Children, Second EditionExpression Analysis of CYFIP1 and CAMKK2 Genes in the Blood of Epileptic and Schizophrenic Patients
2018, Journal of Molecular Neuroscience