Analysis of rare copy number variation in absence epilepsies

Abstract

Objective:To identify shared genes and pathways between common absence epilepsy (AE) subtypes (childhood absence epilepsy [CAE], juvenile absence epilepsy [JAE], and unclassified absence epilepsy [UAE]) that may indicate common mechanisms for absence seizure generation and potentially a diagnostic continuum.Methods:We used high-density single-nucleotide polymorphism arrays to analyze genome-wide rare copy number variation (CNV) in a cohort of 144 children with AEs (95 CAE, 26 UAE, and 23 JAE).Results:We identified CNVs that are known risk factors for AE in 4 patients, including 3x 15q11.2 deletion. We also expanded the phenotype at 4 regions more commonly identified in other neurodevelopmental disorders: 1p36.33 duplication, 1q21.1 deletion, 22q11.2 duplication, and Xp22.31 deletion and duplication. Fifteen patients (10.5%) were found to carry rare CNVs that disrupt genes associated with neuronal development and function (8 CAE, 2 JAE, and 5 UAE). Four categories of protein are each disrupted by several CNVs: (1) synaptic vesicle membrane or vesicle endocytosis, (2) synaptic cell adhesion, (3) synapse organization and motility via actin, and (4) gap junctions. CNVs within these categories are shared across the AE subtypes.Conclusions:Our results have reinforced the complex and heterogeneous nature of the AEs and their potential for shared genetic mechanisms and have highlighted several pathways that may be important in epileptogenesis of absence seizures.

Genetic generalized epilepsy in three siblings with 8q21.13-q22.2 duplication

“…More recently, a connection between sporadic GGEs and CNVs was observed in patients with 15q11.2, 15q13.3 and 16p13.11 microdeletions [8,9]. Moreover, the analysis of rare CNVs exclusively in absence epilepsy has found an association of this phenotype with two additional CNVs disrupting a range of important genes: 1q21.1 and Xp22.31 [10]. Interestingly, potentially causative CNVs are more often observed in patients with GGE plus intellectual disability than in patients with GGE only [11].…”

Drug resistant epilepsy in a young male with Cat Eye Syndrome: a case study

“…Despite neurological abnormalities are frequent in CES, epilepsy is included in the minor features of the syndrome being reported only in about 6% of the cases (3). Recently, Addis et al (28), has shown that 22q11.2 duplication could be one of the gene pathway involved in the epileptogenesis of absence seizures. However, seizure characterization is lacking in CES.…”

Functional Genomics of Epilepsy and Associated Neurodevelopmental Disorders Using Simple Animal Models: From Genes, Molecules to Brain Networks

“…Affordable technology that allows the identification of even small structural genomic alterations [i.e., copy number variations (CNVs)] was key to investigating the genetic basis for common neurodevelopmental disorders. Beginning with transformative studies of people living with autistic spectrum disorders (ASD) (Sebat et al, 2007;Pinto et al, 2010), we have come to understand that individually rare CNVs account for a significant proportion of the incidence not only of autism, but intellectual disability (Cooper et al, 2011), "idiopathic" generalized epilepsies (Mefford et al, 2010;Addis et al, 2016) and schizophrenia (Stefansson et al, 2008;Marshall et al, 2017), particularly where there is overlap between these conditions. Interestingly, genes identified from genome-wide association studies of particular disorders often overlap across disorder categories (Fromer et al, 2014; International League Against Epilepsy Consortium on Complex Epilepsies, 2014; Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014; Turner et al, 2017), suggesting that many of the genes have a broad neurodevelopmental role that may result in a range of recognizable syndromes or phenotypes.…”