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.
Section Complex Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Carolien G F
CG
de Kovel
Holger
H
Trucks
Ingo
I
Helbig
Heather C
HC
Mefford
Carl
C
Baker
Costin
C
Leu
Christian
C
Kluck
Hiltrud
H
Muhle
Sarah
S
von Spiczak
Philipp
P
Ostertag
Tanja
T
Obermeier
Ailing A
AA
Kleefuss-Lie
Kerstin
K
Hallmann
Michael
M
Steffens
Verena
V
Gaus
Karl M
KM
Klein
Hajo M
HM
Hamer
Felix
F
Rosenow
Eva H
EH
Brilstra
Dorothée Kasteleijn-Nolst
DK
Trenité
Marielle E M
ME
Swinkels
Yvonne G
YG
Weber
Iris
I
Unterberger
Fritz
F
Zimprich
Lydia
L
Urak
Martha
M
Feucht
Karoline
K
Fuchs
Rikke S
RS
Møller
Helle
H
Hjalgrim
Peter
P
De Jonghe
Arvid
A
Suls
Ina-Maria
IM
Rückert
Heinz-Erich
HE
Wichmann
Andre
A
Franke
Stefan
S
Schreiber
Peter
P
Nürnberg
Christian E
CE
Elger
Holger
H
Lerche
Ulrich
U
Stephani
Bobby P C
BP
Koeleman
Dick
D
Lindhout
Evan E
EE
Eichler
Thomas
T
Sander
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