16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy

Abstract

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65,046 European population controls (5/393 cases versus 32/65,046 controls; Fisher's exact test P = 2.83 × 10(-6), odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE.

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

“…2 Deletions (MIM: 611913) and duplications (MIM: 614671) of the 16p11.2 600 kb BP4-BP5 region are among the most frequent causes of neurodevelopmental and neuropsychiatric disorders. [2][3][4][5][6][7] They are associated with Rolandic epilepsy 8 and mirror phenotypes on body mass index (BMI), head circumference (HC), and brain volume. [9][10][11][12] The deletion of the distal 16p11.2 220 kb BP2-BP3 locus (MIM: 613444) is likewise enriched in individuals with early-onset obesity and is also associated with developmental delay, intellectual disability, autism spectrum disorders (ASD), and schizophrenia.…”

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

“…All patient and control cohorts included in the analysis are of European origin, have been genetically matched with their respective controls and have been described previously in detail [18][19][20] (Table 1). The epilepsy subtype classifications were based on the terminology proposed by the Commission on Classification and Terminology of the International League against Epilepsy (ILAE) [1].…”

“…Briefly, the epilepsy cohort was composed by 1,366 GGE cases genotyped with the Genome-Wide Human SNP Array 6.0 platform (Affymetrix, Santa Clara, CA, USA) [18] plus 281 and 807 RE and AFE cases, respectively which were genotyped using the Human OmniExpress BeadChip platform (Illumina Inc., San Diego, CA, U.S.A.). The control set was composed of 5,234 samples extracted from the original GGE study and genotyped with the Genome-Wide Human SNP Array 6.0 platform (n= 5,234 [18]) plus 1,512 controls extracted from the original RE study [19] and genotyped using the Human OmniExpress BeadChip platform, totaling 6,746 control individuals (Table 1).…”

“…To investigate the overall contribution of microdeletions in the etiology of common types of epilepsy, we combined all the published microdeletions found in the GGE cohort [18] with the genome-wide microdeletions identified in RE [19] and AFE [20] cohorts (Table 1). In total, we analyzed 134 microdeletions in 2,454 patients with epilepsy compared to 219 microdeletions in 6,746 controls.…”

“…Thus to investigate the deletion burden landscape for common types of epilepsy, here we present the largest combined microdeletion study to date for these traits, examining a total of 9,200 individuals (2,454 epilepsy cases and 6,746 controls). We combined the microdeletions found in a published GGE cohort with unpublished genome-wide microdeletions found in RE [19] and AFE [20] studies. We investigated the combined and sub-type specific burden of microdeletions, as well as their frequency, distribution .…”