Genome-Wide Copy Number Variation in Epilepsy: Novel Susceptibility Loci in Idiopathic Generalized and Focal Epilepsies

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Epilepsy is one of the most common neurological disorders in humans with a prevalence of 1% and a lifetime incidence of 3%. Several genes have been identified in rare autosomal dominant and severe sporadic forms of epilepsy, but the genetic cause is unknown in the vast majority of cases. Copy number variants (CNVs) are known to play an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID), autism, and schizophrenia. Genome-wide studies of copy number variation in epilepsy have not been performed. We have applied whole-genome oligonucleotide array comparative genomic hybridization to a cohort of 517 individuals with various idiopathic, non-lesional epilepsies. We detected one or more rare genic CNVs in 8.9% of affected individuals that are not present in 2,493 controls; five individuals had two rare CNVs. We identified CNVs in genes previously implicated in other neurodevelopmental disorders, including two deletions in AUTS2 and one deletion in CNTNAP2. Therefore, our findings indicate that rare CNVs are likely to contribute to a broad range of generalized and focal epilepsies. In addition, we find that 2.9% of patients carry deletions at 15q11.2, 15q13.3, or 16p13.11, genomic hotspots previously associated with ID, autism, or schizophrenia. In summary, our findings suggest common etiological factors for seemingly diverse diseases such as ID, autism, schizophrenia, and epilepsy.

Vyšlo v časopise: Genome-Wide Copy Number Variation in Epilepsy: Novel Susceptibility Loci in Idiopathic Generalized and Focal Epilepsies. PLoS Genet 6(5): e32767. doi:10.1371/journal.pgen.1000962
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1000962

Souhrn

Zdroje

1. HauserWA

AnnegersJF

RoccaWA

1996 Descriptive epidemiology of epilepsy: contributions of population-based studies from Rochester, Minnesota. Mayo Clin Proc 71 576 586

2. de VriesBB

PfundtR

LeisinkM

KoolenDA

VissersLE

2005 Diagnostic genome profiling in mental retardation. Am J Hum Genet 77 606 616

3. FriedmanJM

BarossA

DelaneyAD

AllyA

ArbourL

2006 Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation. Am J Hum Genet 79 500 513

4. KoolenDA

VissersLE

PfundtR

de LeeuwN

KnightSJ

2006 A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat Genet 38 999 1001

5. SagooG

ButterworthA

SandersonS

Shaw-SmithC

HigginsJ

2009 Array CGH in patients with learning disability (mental retardation) and congenital anomalies: updated systematic review and meta-analysis of 19 studies and 13,926 subjects. Genet Med 11 139 146

6. ShafferLG

KashorkCD

SalekiR

RoremE

SundinK

2006 Targeted genomic microarray analysis for identification of chromosome abnormalities in 1500 consecutive clinical cases. J Pediatr 149 98 102

7. SharpAJ

HansenS

SelzerRR

ChengZ

ReganR

2006 Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet 38 1038 1042

8. Shaw-SmithC

PittmanAM

WillattL

MartinH

RickmanL

2006 Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nat Genet 38 1032 1037

9. ChristianSL

BruneCW

SudiJ

KumarRA

LiuS

2008 Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder. Biol Psychiatry 63 1111 1117

10. KumarRA

KaraMohamedS

SudiJ

ConradDF

BruneC

2008 Recurrent 16p11.2 microdeletions in autism. Hum Mol Genet 17 628 638

11. MarshallCR

NoorA

VincentJB

LionelAC

FeukL

2008 Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82 477 488

12. SebatJ

LakshmiB

MalhotraD

TrogeJ

Lese-MartinC

2007 Strong association of de novo copy number mutations with autism. Science 316 445 449

13. SzatmariP

PatersonAD

ZwaigenbaumL

RobertsW

BrianJ

2007 Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 39 319 328

14. WeissLA

ShenY

KornJM

ArkingDE

MillerDT

2008 Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 358 667 675

15. International Schizophrenia Consortium 2008 Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455 237 241

16. KirovG

GrozevaD

NortonN

IvanovD

MantripragadaKK

2009 Support for the involvement of large cnvs in the pathogenesis of schizophrenia. Hum Mol Genet 18 1497 1503

17. StefanssonH

RujescuD

CichonS

PietilainenOP

IngasonA

2008 Large recurrent microdeletions associated with schizophrenia. Nature 455 232 236

18. WalshT

McClellanJM

McCarthySE

AddingtonAM

PierceSB

2008 Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320 539 543

19. XuB

RoosJL

LevyS

van RensburgEJ

GogosJA

2008 Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet 40 880 885

20. de KovelCG

TrucksH

HelbigI

MeffordHC

BakerC

2009 Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain

21. DibbensLM

MullenS

HelbigI

MeffordHC

BaylyMA

2009 Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance. Hum Mol Genet 18 3626 3631

22. HelbigI

MeffordHC

SharpAJ

GuipponiM

FicheraM

2009 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet 41 160 162

23. BaileyJA

GuZ

ClarkRA

ReinertK

SamonteRV

2002 Recent segmental duplications in the human genome. Science 297 1003 1007

24. ItsaraA

CooperGM

BakerC

GirirajanS

LiJ

2009 Population analysis of large copy number variants and hotspots of human genetic disease. Am J Hum Genet 84 148 161

25. Ben-ShacharS

LanpherB

GermanJR

QasaymehM

PotockiL

2009 Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders. J Med Genet 46 382 388

26. HannesFD

SharpAJ

MeffordHC

de RavelT

RuivenkampCA

2009 Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant. J Med Genet 46 223 232

27. MeffordHC

CooperGM

ZerrT

SmithJD

BakerC

2009 A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease. Genome Res 19 1579 1585

28. MillerDT

ShenY

WeissLA

KornJ

AnselmI

2008 Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatirc disorders. J Med Genet 46 242 248

29. NeedAC

GeD

WealeME

MaiaJ

FengS

2009 A genome-wide investigation of SNPs and CNVs in schizophrenia. PLoS Genet 5 e1000373 doi:10.1371/journal.pgen.1000373

30. PagnamentaAT

WingK

AkhaES

KnightSJ

BolteS

2009 A 15q13.3 microdeletion segregating with autism. Eur J Hum Genet 17 687 692

31. SharpAJ

MeffordHC

LiK

BakerC

SkinnerC

2008 A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet 40 322 328

32. UllmannR

TurnerG

KirchhoffM

ChenW

TongeB

2007 Array CGH identifies reciprocal 16p13.1 duplications and deletions that predispose to autism and/or mental retardation. Hum Mutat 28 674 682

33. Brunetti-PierriN

BergJS

ScagliaF

BelmontJ

BacinoCA

2008 Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat Genet 40 1466 1471

34. MeffordHC

SharpAJ

BakerC

ItsaraA

JiangZ

2008 Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med 359 1685 1699

35. BijlsmaEK

GijsbersAC

Schuurs-HoeijmakersJH

van HaeringenA

Fransen van de PutteDE

2009 Extending the phenotype of recurrent rearrangements of 16p11.2: Deletions in mentally retarded patients without autism and in normal individuals. Eur J Med Genet 52 77 87

36. BochukovaEG

HuangN

KeoghJ

HenningE

PurmannC

2010 Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 463 666 670

37. McCarthySE

MakarovV

KirovG

AddingtonAM

McClellanJ

2009 Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet 41 1223 1227

38. GirirajanS

RosenfeldJA

CooperGM

AntonacciF

SiswaraP

2010 A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nat Genet 42 203 209

39. DooseH

HahnA

NeubauerBA

PistohlJ

StephaniU

2001 Atypical “benign” partial epilepsy of childhood or pseudo-lennox syndrome. Part II: family study. Neuropediatrics 32 9 13

40. van BonBW

MeffordHC

MentenB

KoolenDA

SharpAJ

2009 Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. J Med Genet 46 511 523

41. BonatiMT

CombiR

AsseltaR

DugaS

MalcovatiM

2002 Exclusion of linkage of nine neuronal nicotinic acetylcholine receptor subunit genes expressed in brain in autosomal dominant nocturnal frontal lobe epilepsy in four unrelated families. J Neurol 249 967 974

42. TaskeNL

WilliamsonMP

MakoffA

BateL

CurtisD

2002 Evaluation of the positional candidate gene CHRNA7 at the juvenile myoclonic epilepsy locus (EJM2) on chromosome 15q13-14. Epilepsy Res 49 157 172

43. ShinawiM

SchaafCP

BhattSS

XiaZ

PatelA

2009 A small recurrent deletion within 15q13.3 is associated with a range of neurodevelopmental phenotypes. Nat Genet 41 1269 1271

44. ButlerMG

BittelDC

KibiryevaN

TalebizadehZ

ThompsonT

2004 Behavioral differences among subjects with Prader-Willi syndrome and type I or type II deletion and maternal disomy. Pediatrics 113 565 573

45. HartleySL

MacleanWEJr

ButlerMG

ZarconeJ

ThompsonT

2005 Maladaptive behaviors and risk factors among the genetic subtypes of Prader-Willi syndrome. Am J Med Genet A 136 140 145

46. SahooT

PetersSU

MadduriNS

GlazeDG

GermanJR

2006 Microarray based comparative genomic hybridization testing in deletion bearing patients with Angelman syndrome: genotype-phenotype correlations. J Med Genet 43 512 516

47. ChristiansenJ

DyckJD

ElyasBG

LilleyM

BamforthJS

2004 Chromosome 1q21.1 contiguous gene deletion is associated with congenital heart disease. Circ Res 94 1429 1435

48. GreenwaySC

PereiraAC

LinJC

DePalmaSR

IsraelSJ

2009 De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot. Nat Genet 41 931 935

49. RedonR

IshikawaS

FitchKR

FeukL

PerryGH

2006 Global variation in copy number in the human genome. Nature 444 444 454

50. AlarconM

AbrahamsBS

StoneJL

DuvallJA

PerederiyJV

2008 Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet 82 150 159

51. ArkingDE

CutlerDJ

BruneCW

TeslovichTM

WestK

2008 A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am J Hum Genet 82 160 164

52. BakkalogluB

O'RoakBJ

LouviA

GuptaAR

AbelsonJF

2008 Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am J Hum Genet 82 165 173

53. FriedmanJI

VrijenhoekT

MarkxS

JanssenIM

van der VlietWA

2008 CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy. Mol Psychiatry 13 261 266

54. KalscheuerVM

FitzPatrickD

TommerupN

BuggeM

NiebuhrE

2007 Mutations in autism susceptibility candidate 2 (AUTS2) in patients with mental retardation. Hum Genet 121 501 509

55. SultanaR

YuCE

YuJ

MunsonJ

ChenD

2002 Identification of a novel gene on chromosome 7q11.2 interrupted by a translocation breakpoint in a pair of autistic twins. Genomics 80 129 134

56. ClaesL

CeulemansB

AudenaertD

SmetsK

LofgrenA

2003 De novo SCN1A mutations are a major cause of severe myoclonic epilepsy of infancy. Hum Mutat 21 615 621

57. EscaygA

MacDonaldBT

MeislerMH

BaulacS

HuberfeldG

2000 Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nat Genet 24 343 345

58. FujiwaraT

2006 Clinical spectrum of mutations in SCN1A gene: severe myoclonic epilepsy in infancy and related epilepsies. Epilepsy Res 70 Suppl 1 S223 230

59. DooseH

LunauH

CastiglioneE

WaltzS

1998 Severe idiopathic generalized epilepsy of infancy with generalized tonic-clonic seizures. Neuropediatrics 29 229 238

60. HelbigI

MeffordHC

SharpAJ

GuipponiM

FicheraM

2009 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet 41 160 162

61. ILAE 1989 Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 30 389 399

62. DayN

HemmaplardhA

ThurmanRE

StamatoyannopoulosJA

NobleWS

2007 Unsupervised segmentation of continuous genomic data. Bioinformatics 23 1424 1426