Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes.
Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions.
Heinzen
Erin L
EL
Center for Human Genome Variation, School of Medicine, Duke University, Durham, NC 27708, USA.
Radtke
Rodney A
RA
Urban
Thomas J
TJ
Cavalleri
Gianpiero L
GL
Depondt
Chantal
C
Need
Anna C
AC
Walley
Nicole M
NM
Nicoletti
Paola
P
Ge
Dongliang
D
Catarino
Claudia B
CB
Duncan
John S
JS
Kasperaviciūte
Dalia
D
Tate
Sarah K
SK
Caboclo
Luis O
LO
Sander
Josemir W
JW
Clayton
Lisa
L
Linney
Kristen N
KN
Shianna
Kevin V
KV
Gumbs
Curtis E
CE
Smith
Jason
J
Cronin
Kenneth D
KD
Maia
Jessica M
JM
Doherty
Colin P
CP
Pandolfo
Massimo
M
Leppert
David
D
Middleton
Lefkos T
LT
Gibson
Rachel A
RA
Johnson
Michael R
MR
Matthews
Paul M
PM
Hosford
David
D
Kälviäinen
Reetta
R
Eriksson
Kai
K
Kantanen
Anne-Mari
AM
Dorn
Thomas
T
Hansen
Jörg
J
Krämer
Günter
G
Steinhoff
Bernhard J
BJ
Wieser
Heinz-Gregor
HG
Zumsteg
Dominik
D
Ortega
Marcos
M
Wood
Nicholas W
NW
Huxley-Jones
Julie
J
Mikati
Mohamad
M
Gallentine
William B
WB
Husain
Aatif M
AM
Buckley
Patrick G
PG
Stallings
Ray L
RL
Podgoreanu
Mihai V
MV
Delanty
Norman
N
Sisodiya
Sanjay M
SM
Goldstein
David B
DB
D002885:Chromosomes, Human, Pair 16; D004198:Disease Susceptibility; D004827:Epilepsy / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009693:Nucleic Acid Hybridization / Q000235:genetics; D017384:Sequence Deletion; D013577:Syndrome
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