Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies.
Idiopathic generalized epilepsies account for 30% of all epilepsies. Despite a predominant genetic aetiology, the genetic factors predisposing to idiopathic generalized epilepsies remain elusive. Studies of structural genomic variations have revealed a significant excess of recurrent microdeletions at 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 in various neuropsychiatric disorders including autism, intellectual disability and schizophrenia. Microdeletions at 15q13.3 have recently been shown to constitute a strong genetic risk factor for common idiopathic generalized epilepsy syndromes, implicating that other recurrent microdeletions may also be involved in epileptogenesis. This study aimed to investigate the impact of five microdeletions at the genomic hotspot regions 1q21.1, 15q11.2, 16p11.2, 16p13.11 and 22q11.2 on the genetic risk to common idiopathic generalized epilepsy syndromes. The candidate microdeletions were assessed by high-density single nucleotide polymorphism arrays in 1234 patients with idiopathic generalized epilepsy from North-western Europe and 3022 controls from the German population. Microdeletions were validated by quantitative polymerase chain reaction and their breakpoints refined by array comparative genomic hybridization. In total, 22 patients with idiopathic generalized epilepsy (1.8%) carried one of the five novel microdeletions compared with nine controls (0.3%) (odds ratio = 6.1; 95% confidence interval 2.8-13.2; chi(2) = 26.7; 1 degree of freedom; P = 2.4 x 10(-7)). Microdeletions were observed at 1q21.1 [Idiopathic generalized epilepsy (IGE)/control: 1/1], 15q11.2 (IGE/control: 12/6), 16p11.2 IGE/control: 1/0, 16p13.11 (IGE/control: 6/2) and 22q11.2 (IGE/control: 2/0). Significant associations with IGEs were found for the microdeletions at 15q11.2 (odds ratio = 4.9; 95% confidence interval 1.8-13.2; P = 4.2 x 10(-4)) and 16p13.11 (odds ratio = 7.4; 95% confidence interval 1.3-74.7; P = 0.009). Including nine patients with idiopathic generalized epilepsy in this cohort with known 15q13.3 microdeletions (IGE/control: 9/0), parental transmission could be examined in 14 families. While 10 microdeletions were inherited (seven maternal and three paternal transmissions), four microdeletions occurred de novo at 15q13.3 (n = 1), 16p13.11 (n = 2) and 22q11.2 (n = 1). Eight of the transmitting parents were clinically unaffected, suggesting that the microdeletion itself is not sufficient to cause the epilepsy phenotype. Although the microdeletions investigated are individually rare (<1%) in patients with idiopathic generalized epilepsy, they collectively seem to account for a significant fraction of the genetic variance in common idiopathic generalized epilepsy syndromes. The present results indicate an involvement of microdeletions at 15q11.2 and 16p13.11 in epileptogenesis and strengthen the evidence that recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 confer a pleiotropic susceptibility effect to a broad range of neuropsychiatric disorders.
de Kovel
Carolien G F
CG
Section Complex Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Trucks
Holger
H
Helbig
Ingo
I
Mefford
Heather C
HC
Baker
Carl
C
Leu
Costin
C
Kluck
Christian
C
Muhle
Hiltrud
H
von Spiczak
Sarah
S
Ostertag
Philipp
P
Obermeier
Tanja
T
Kleefuss-Lie
Ailing A
AA
Hallmann
Kerstin
K
Steffens
Michael
M
Gaus
Verena
V
Klein
Karl M
KM
Hamer
Hajo M
HM
Rosenow
Felix
F
Brilstra
Eva H
EH
Trenité
Dorothée Kasteleijn-Nolst
DK
Swinkels
Marielle E M
ME
Weber
Yvonne G
YG
Unterberger
Iris
I
Zimprich
Fritz
F
Urak
Lydia
L
Feucht
Martha
M
Fuchs
Karoline
K
Møller
Rikke S
RS
Hjalgrim
Helle
H
De Jonghe
Peter
P
Suls
Arvid
A
Rückert
Ina-Maria
IM
Wichmann
Heinz-Erich
HE
Franke
Andre
A
Schreiber
Stefan
S
Nürnberg
Peter
P
Elger
Christian E
CE
Lerche
Holger
H
Stephani
Ulrich
U
Koeleman
Bobby P C
BP
Lindhout
Dick
D
Eichler
Evan E
EE
Sander
Thomas
T
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D015331:Cohort Studies; D004829:Epilepsy, Generalized / Q000209:etiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D010375:Pedigree; D055815:Young Adult