Copy Number Variants and Epilepsy: New Emerging Syndromes

  • Antonietta CoppolaEmail author
  • Maurizio Elia
Part of the Contemporary Clinical Neuroscience book series (CCNE)


In the last 10 years, advances in the genetic techniques including oligonucleotide array and the following large scale studies have yielded to the identification of recurrent copy number variants (CNVs) associated with epilepsy. Among these a small number has been increasingly reported in association with a distinct epileptic phenotype, delineating emerging epileptic syndromes. To date, none of these CNVs underlying a specific epileptic condition has been included in the ILAE Classification of the Epileptic Syndromes as a distinct form. However once the features and prognosis of these conditions have been completely delineated a proposal for new epileptic syndromes should be considered.


Epilepsy Copy number variation 2q24.4 del 5q14.3 del 6q terminal del 14q12 del and dup 15q13.3 del Xp11.22-11.23 dup SCN1A 


  1. Ariani F et al (2008) FOXG1 is responsible for the congenital variant of Rett syndrome. Am J Hum Genet 83(1):89–93PubMedCentralPubMedCrossRefGoogle Scholar
  2. Ben-Shachar S et al (2009) Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders. J Med Genet 46(6):382–388PubMedCentralPubMedCrossRefGoogle Scholar
  3. Berg AT et al (2010) Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 51(4):676–685PubMedCrossRefGoogle Scholar
  4. Bertini V et al (2006) Isolated 6q terminal deletions: an emerging new syndrome. Am J Med Genet A 140(1):74–81PubMedCrossRefGoogle Scholar
  5. Broli M et al (2011) Definition of the neurological phenotype associated with dup (X)(p11.22-p11.23). Epileptic Disord 13(3):240–251PubMedGoogle Scholar
  6. Brunetti-Pierri N et al (2011) Duplications of FOXG1 in 14q12 are associated with developmental epilepsy, mental retardation, and severe speech impairment. Eur J Hum Genet 19(1):102–107PubMedCentralPubMedCrossRefGoogle Scholar
  7. Cardoso C et al (2009) Periventricular heterotopia, mental retardation, and epilepsy associated with 5q14.3-q15 deletion. Neurology 72(9):784–792PubMedCrossRefGoogle Scholar
  8. Coppola A et al (2013) Different electroclinical picture of generalized epilepsy in two families with 15q13.3 microdeletion. Epilepsia 54(5):e69–e73PubMedCrossRefGoogle Scholar
  9. Davidsson J et al (2008) Deletion of the SCN gene cluster on 2q24.4 is associated with severe epilepsy: an array-based genotype-phenotype correlation and a comprehensive review of previously published cases. Epilepsy Res 81(1):69–79PubMedCrossRefGoogle Scholar
  10. Dibbens LM et al (2009) Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance. Hum Mol Genet 18(19):3626–3631PubMedCentralPubMedCrossRefGoogle Scholar
  11. Elia M et al (2006) 6q terminal deletion syndrome associated with a distinctive EEG and clinical pattern: a report of five cases. Epilepsia 47(5):830–838PubMedCrossRefGoogle Scholar
  12. Endris V et al (2010) Homozygous loss of CHRNA7 on chromosome 15q13.3 causes severe encephalopathy with seizures and hypotonia. Am J Med Genet A 152A(11):2908–2911PubMedCrossRefGoogle Scholar
  13. Engels H et al (2009) A novel microdeletion syndrome involving 5q14.3-q15: clinical and molecular cytogenetic characterization of three patients. Eur J Hum Genet 17(12):1592–1599PubMedCentralPubMedCrossRefGoogle Scholar
  14. Giorda R et al (2009) Complex segmental duplications mediate a recurrent dup(X)(p11.22-p11.23) associated with mental retardation, speech delay, and EEG anomalies in males and females. Am J Hum Genet 85(3):394–400PubMedCentralPubMedCrossRefGoogle Scholar
  15. Heinzen EL et al (2010) Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes. Am J Hum Genet 86(5):707–718PubMedCentralPubMedCrossRefGoogle Scholar
  16. Helbig I et al (2009) 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet 41(2):160–162PubMedCentralPubMedCrossRefGoogle Scholar
  17. Kasperaviciute D et al (2010) Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study. Brain 133(Pt 7):2136–2147PubMedCentralPubMedCrossRefGoogle Scholar
  18. Le Meur N et al (2010) MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations. J Med Genet 47(1):22–29PubMedCentralPubMedCrossRefGoogle Scholar
  19. Lee JY, Cho YH, Hallford G (2011) Delineation of subtelomeric deletion of the long arm of chromosome 6. Ann Hum Genet 75(6):755–764PubMedCrossRefGoogle Scholar
  20. Lepichon JB et al (2010) A 15q13.3 homozygous microdeletion associated with a severe neurodevelopmental disorder suggests putative functions of the TRPM1, CHRNA7, and other homozygously deleted genes. Am J Med Genet A 152A(5):1300–1304PubMedCrossRefGoogle Scholar
  21. Madia F et al (2006) Cryptic chromosome deletions involving SCN1A in severe myoclonic epilepsy of infancy. Neurology 67(7):1230–1235PubMedCrossRefGoogle Scholar
  22. Marini C et al (2009) SCN1A duplications and deletions detected in Dravet syndrome: implications for molecular diagnosis. Epilepsia 50(7):1670–1678PubMedCrossRefGoogle Scholar
  23. Marshall CR et al (2008) Infantile spasms is associated with deletion of the MAGI2 gene on chromosome 7q11.23-q21.11. Am J Hum Genet 83(1):106–111PubMedCentralPubMedCrossRefGoogle Scholar
  24. Masurel-Paulet A et al (2010) Delineation of 15q13.3 microdeletions. Clin Genet 78(2):149–161PubMedCrossRefGoogle Scholar
  25. Mencarelli MA et al (2009) 14q12 Microdeletion syndrome and congenital variant of Rett syndrome. Eur J Med Genet 52(2–3):148–152PubMedCrossRefGoogle Scholar
  26. Mizugishi K et al (1998) Interstitial deletion of chromosome 7q in a patient with Williams syndrome and infantile spasms. J Hum Genet 43(3):178–181PubMedCrossRefGoogle Scholar
  27. Muhle H et al (2011) Absence seizures with intellectual disability as a phenotype of the 15q13.3 microdeletion syndrome. Epilepsia 52(12):e194–e198PubMedCentralPubMedCrossRefGoogle Scholar
  28. Mulley JC, Dibbens LM (2009) Chipping away at the common epilepsies with complex genetics: the 15q13.3 microdeletion shows the way. Genome Med 1(3):33PubMedCentralPubMedCrossRefGoogle Scholar
  29. Mulley JC, Mefford HC (2011) Epilepsy and the new cytogenetics. Epilepsia 52(3):423–432PubMedCentralPubMedCrossRefGoogle Scholar
  30. Mulley JC et al (2006) A new molecular mechanism for severe myoclonic epilepsy of infancy: exonic deletions in SCN1A. Neurology 67(6):1094–1095PubMedCrossRefGoogle Scholar
  31. Pereira S et al (2004) Severe epilepsy, retardation, and dysmorphic features with a 2q deletion including SCN1A and SCN2A. Neurology 63(1):191–192PubMedCrossRefGoogle Scholar
  32. Poduri A, Lowenstein D (2011) Epilepsy genetics—past, present, and future. Curr Opin Genet Dev 21(3):325–332PubMedCentralPubMedCrossRefGoogle Scholar
  33. Potthoff MJ, Olson EN (2007) MEF2: a central regulator of diverse developmental programs. Development 134(23):4131–4140PubMedCrossRefGoogle Scholar
  34. Scheffer IE, Berkovic SF (2010) Copy number variants–an unexpected risk factor for the idiopathic generalized epilepsies. Brain 133(Pt 1):7–8PubMedCrossRefGoogle Scholar
  35. Sharp AJ et al (2008) A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet 40(3):322–328PubMedCentralPubMedCrossRefGoogle Scholar
  36. Shinawi M et al (2009) A small recurrent deletion within 15q13.3 is associated with a range of neurodevelopmental phenotypes. Nat Genet 41(12):1269–1271PubMedCentralPubMedCrossRefGoogle Scholar
  37. Striano P et al (2006) Clinical phenotype and molecular characterization of 6q terminal deletion syndrome: Five new cases. Am J Med Genet A 140(18):1944–1949PubMedCrossRefGoogle Scholar
  38. Striano P et al (2011a) Clinical significance of rare copy number variations in epilepsy: A case-control survey using microarray-based comparative genomic hybridization. Arch Neurol 69(3):322–30Google Scholar
  39. Striano P et al (2011b) West syndrome associated with 14q12 duplications harboring FOXG1. Neurology 76(18):1600–1602Google Scholar
  40. Suls A et al (2006) Microdeletions involving the SCN1A gene may be common in SCN1A-mutation-negative SMEI patients. Hum Mutat 27(9):914–920PubMedCrossRefGoogle Scholar
  41. van Bon BW et al (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(8):511–523PubMedCentralPubMedCrossRefGoogle Scholar
  42. van Bon BW et al (2010) The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype. Eur J Hum Genet 18(2):163–170PubMedCentralPubMedCrossRefGoogle Scholar
  43. Zweier M et al (2010) Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression. Hum Mutat 31(6):722–733PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Epilepsy Centre, Neurology DepartmentFederico II UniversityNaplesItaly
  2. 2.Oasi Institute for Research on Mental Retardation and Brain AgingTroinaItaly

Personalised recommendations