title: Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes.
abstract: 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.
authors.affiliation: Center for Human Genome Variation, School of Medicine, Duke University, Durham, NC 27708, USA.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Heinzen
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Radtke
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Urban
authors.forename: Gianpiero L
authors.initials: GL
authors.lastname: Cavalleri
authors.forename: Chantal
authors.initials: C
authors.lastname: Depondt
authors.forename: Anna C
authors.initials: AC
authors.lastname: Need
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Walley
authors.forename: Paola
authors.initials: P
authors.lastname: Nicoletti
authors.forename: Dongliang
authors.initials: D
authors.lastname: Ge
authors.forename: Claudia B
authors.initials: CB
authors.lastname: Catarino
authors.forename: John S
authors.initials: JS
authors.lastname: Duncan
authors.forename: Dalia
authors.initials: D
authors.lastname: Kasperaviciūte
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Tate
authors.forename: Luis O
authors.initials: LO
authors.lastname: Caboclo
authors.forename: Josemir W
authors.initials: JW
authors.lastname: Sander
authors.forename: Lisa
authors.initials: L
authors.lastname: Clayton
authors.forename: Kristen N
authors.initials: KN
authors.lastname: Linney
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Shianna
authors.forename: Curtis E
authors.initials: CE
authors.lastname: Gumbs
authors.forename: Jason
authors.initials: J
authors.lastname: Smith
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Cronin
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Maia
authors.forename: Colin P
authors.initials: CP
authors.lastname: Doherty
authors.forename: Massimo
authors.initials: M
authors.lastname: Pandolfo
authors.forename: David
authors.initials: D
authors.lastname: Leppert
authors.forename: Lefkos T
authors.initials: LT
authors.lastname: Middleton
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Gibson
authors.forename: Michael R
authors.initials: MR
authors.lastname: Johnson
authors.forename: Paul M
authors.initials: PM
authors.lastname: Matthews
authors.forename: David
authors.initials: D
authors.lastname: Hosford
authors.forename: Reetta
authors.initials: R
authors.lastname: Kälviäinen
authors.forename: Kai
authors.initials: K
authors.lastname: Eriksson
authors.forename: Anne-Mari
authors.initials: AM
authors.lastname: Kantanen
authors.forename: Thomas
authors.initials: T
authors.lastname: Dorn
authors.forename: Jörg
authors.initials: J
authors.lastname: Hansen
authors.forename: Günter
authors.initials: G
authors.lastname: Krämer
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Steinhoff
authors.forename: Heinz-Gregor
authors.initials: HG
authors.lastname: Wieser
authors.forename: Dominik
authors.initials: D
authors.lastname: Zumsteg
authors.forename: Marcos
authors.initials: M
authors.lastname: Ortega
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.forename: Julie
authors.initials: J
authors.lastname: Huxley-Jones
authors.forename: Mohamad
authors.initials: M
authors.lastname: Mikati
authors.forename: William B
authors.initials: WB
authors.lastname: Gallentine
authors.forename: Aatif M
authors.initials: AM
authors.lastname: Husain
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Buckley
authors.forename: Ray L
authors.initials: RL
authors.lastname: Stallings
authors.forename: Mihai V
authors.initials: MV
authors.lastname: Podgoreanu
authors.forename: Norman
authors.initials: N
authors.lastname: Delanty
authors.forename: Sanjay M
authors.initials: SM
authors.lastname: Sisodiya
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
mesh_terms: 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
references.citation: Arch Neurol. 2002 Jul;59(7):1137-41
references.pmid: 12117362
references.citation: Bioinformatics. 2009 Jul 15;25(14):1754-60
references.pmid: 19451168
references.citation: Nat Genet. 2009 Feb;41(2):160-2
references.pmid: 19136953
references.citation: Int Rev Neurobiol. 2008;83:347-83
references.pmid: 18929092
references.citation: J Med Genet. 2009 Apr;46(4):223-32
references.pmid: 18550696
references.citation: Epilepsy Res. 2008 Jul;80(1):1-8
references.pmid: 18440780
references.citation: N Engl J Med. 2008 Oct 16;359(16):1685-99
references.pmid: 18784092
references.citation: Nat Genet. 2001 May;28(1):49-52
references.pmid: 11326275
references.citation: Nat Genet. 2002 Jun;31(2):184-9
references.pmid: 11992121
references.citation: Hum Mol Genet. 2002 May 1;11(9):1119-28
references.pmid: 11978770
references.citation: Nature. 2008 Sep 11;455(7210):232-6
references.pmid: 18668039
references.citation: J Med Genet. 2009 Aug;46(8):511-23
references.pmid: 19372089
references.citation: Science. 2008 Apr 25;320(5875):539-43
references.pmid: 18369103
references.citation: Am J Hum Genet. 2002 Feb;70(2):530-6
references.pmid: 11748509
references.citation: Hum Mol Genet. 2009 Oct 1;18(19):3626-31
references.pmid: 19592580
references.citation: Nat Genet. 2002 Mar;30(3):335-41
references.pmid: 11810107
references.citation: N Engl J Med. 2008 Feb 14;358(7):667-75
references.pmid: 18184952
references.citation: Brain. 2010 Jan;133(Pt 1):23-32
references.pmid: 19843651
references.citation: Hum Mol Genet. 2008 Aug 15;17(16):2441-55
references.pmid: 18469343
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Neurology. 2006 Aug 22;67(4):687-90
references.pmid: 16924025
references.citation: Brain. 1999 May;122 ( Pt 5):817-25
references.pmid: 10355668
references.citation: Bioinformatics. 2009 Aug 15;25(16):2078-9
references.pmid: 19505943
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 29;106(39):16746-51
references.pmid: 19805367
references.citation: PLoS Genet. 2009 Feb;5(2):e1000373
references.pmid: 19197363