Burden Analysis of Rare Microdeletions Suggests a Strong Impact of Neurodevelopmental Genes in Genetic Generalised Epilepsies

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.

Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy

“…We obtained detailed phenotypic information on a previously reported patient (EC-CAE300). 8 The common phenotypic features of both patients identified through the Lyon and Geneva database were absences and ID. Patient 9A117 has a very complex cytogenetic profile including, in addition to the homogeneous deletion involving RORB, abnormal chromosomes in mosaic state.…”

“…We also added detailed clinical data on a previously reported patient with childhood absence epilepsy (EC-CAE300), who was revisited during this study. 8 Finally, a follow-up cohort of 100 patients with GGE was screened with Sanger sequencing.…”

“…In recent genome-wide studies, rare recurrent copy number variants (CNVs) that are important risk factors for other neuropsychiatric disorders were present in about 4% of the generalized epilepsies. [6][7][8] Several single cases with non-recurrent deletions have also been reported in otherwise common epilepsies accounting for up to 5% of patients studied. The genes located within these CNVs deserve further study given that they are potential candidates for susceptibility to GGE.…”

Multiplex families with epilepsy

“…In support of this was the discovery that rare inherited copy number variants can increase risk for different epilepsy syndromes. 16,17 To pragmatically bridge the divide between classical large family and epidemiologic approaches, this study adopted an intermediate strategy. We conducted an intensive clinical genetic survey of 211 multiplex families ascertained from the ethnically diverse Israeli population.…”

Heterogeneous Contribution of Microdeletions in the Development of Common Generalized and Focal epilepsies

“…In this regard, twelve genomic regions prone to exhibit copy number rearrangements or CNV "hotspot loci" have been reported to increase the risk for neurodevelopmental disorders [14], seven of them directly associated to epilepsy including 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p12, 16p13.11, and 22q11.2 to GGE [15][16][17][18], and also 16p11.2 to RE and AFE [19 20]. The relationship to epilepsy of the remaining 5 loci, namely 3q29, 10q22q23, 15q24, 17q12, and 17q21.3 remains to be elucidated.…”