Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies.

Dennis Lal,Christian Gieger,Felix Rosenow,Wolfram S Kunz,Helle Hjalgrim,Hiltrud Muhle,Verena Gaus,Claudia Schurmann,Anja C M Sonsma,Peter De Jonghe,Ulrich Stephani,Yvonne G Weber,Ulf Schminke,Fritz Zimprich,Holger Lerche,Rikke S Møller,Bettina Schmitz,Christian E Elger,Konstantin Strauch,Holger Trucks,Eva M Reinthaler,Arvid Suls,Martha Feucht,Dick Lindhout,Wolfgang Lieb,Claudia Kapser,Rainer Surges,Thomas Sander,Herbert Schulz,Bernd A Neubauer,Peter Nürnberg,Ann-Kathrin Ruppert,Ingo Helbig,Bobby P C Koeleman ,André Franke ,Karl Martin Klein ,Christoph Schankin ,Dorothée Kasteleijn‐Nolst Trenité ,Carolien G.f De Kovel

doi:10.1371/journal.pgen.1005226

Abstract

Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.

Highlights

The epilepsies comprise a clinically heterogeneous group of neurological disorders defined by recurrent spontaneous seizures due to paroxysmal excessive and synchronous neuronal activity in the brain [1]
Our results revealed a 2-fold excess of microdeletions in genetic generalised epilepsies (GGEs) patients relative to the population controls, 2) a 7-fold increased burden for known hotspot microdeletions (15q11.2, 15q13.3, 16p13.11, 22q11.2) previously associated with a wide range of neurodevelopmental disorders, and 3) a more than 4-fold enrichment of microdeletions carrying a gene implicated in neurodevelopmental disorders
Our findings reinforce emerging evidence that genes affected by microdeletions in GGE patients have a strong impact in fundamental neurodevelopmental processes and dissect novel candidate genes involved in epileptogenesis

Summary

Introduction

The epilepsies comprise a clinically heterogeneous group of neurological disorders defined by recurrent spontaneous seizures due to paroxysmal excessive and synchronous neuronal activity in the brain [1]. The genetic generalised epilepsies (GGEs) represent the most common group of epilepsies with predominant genetic aetiology, accounting for 20% of all epilepsies [3] Their clinical features are characterised by unprovoked generalised seizures with age-related onset, generalised spike and wave discharges on the electroencephalogram and no evidence for an acquired cause [4,5]. Despite their strong familial aggregation and heritability [6,7,8,9], the genetic architecture of common GGE syndromes is likely to display a biological spectrum, in which a small fraction (1– 2%) follows monogenic inheritance, whereas the majority of GGE patients presumably display an oligo-/polygenic predisposition with extensive genetic heterogeneity [10]. Causative mutations for rare GGE with monogenic inheritance have been identified in genes primarily affecting neuronal excitability, synaptic transmission, and neurodevelopmental processes [11,12], the genetic basis of the majority of patients with GGE remains largely unsolved

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