Epilepsy: Genetics


At least 40% of all epilepsies have a genetic basis. Some forms of epilepsy have a simple Mendelian mode of inheritance, but these are very rare. The more common forms have a complex genetic background potentially involving several genes. Traditional methodologies for finding disease genes have been relatively successful for Mendelian forms of epilepsy. Although these approaches have been less successful for the common, complex epilepsies, it has still been possible to identify some disease‐associated genes. Most of the genes involved in epilepsy encode ion channel subunits making epilepsy an example of a ‘channelopathy’. The introduction of next generation genetic technologies has increased hope of identifying the specific genetic variants which contribute to individual susceptibility to common and Mendelian epilepsy; and with this comes hope of new deoxyribonucleic acid (DNA)‐based diagnostic techniques and the development of more specific therapies.

Key Concepts:

  • A large proportion of epilepsies have a genetic basis.

  • The majority of genetic epilepsies demonstrate a complex mode of inheritance.

  • Complex inheritance indicates that disease is caused by a combination of genetic changes potentially combined with nongenetic factors.

  • Mode of inheritance can vary between families.

  • Epilepsy is primarily a channelopathy; a disease caused by dysfunction of ion channels.

  • Some genetic changes directly cause disease whereas others alter disease susceptibility.

  • Genetic changes in the same gene can result in different epilepsies.

  • New genetic technologies will facilitate the identification of genetic changes causing both Mendelian and complex epilepsy.

Keywords: epilepsy; neurology; neurogenetics; ion channels; genetic diseases; myoclonin; receptor; Mendelian; complex


Annesi F, Gambardella A, Michelucci R et al. (2007) Mutational analysis of EFHC1 gene in Italian families with juvenile myoclonic epilepsy. Epilepsia 48(9): 1686–1690.

Annesi G, Gambardella A, Carrideo S et al. (2003) Two novel SCN1A missense mutations in generalized epilepsy with febrile seizures plus. Epilepsia 44(9): 1257–1258.

Aridon P, Marini C, Di Resta C et al. (2006) Increased sensitivity of the neuronal nicotinic receptor alpha 2 subunit causes familial epilepsy with nocturnal wandering and ictal fear. American Journal of Human Genetics 79(2): 342–350.

Audenaert D, Claes L, Ceulemans B et al. (2003) A deletion in SCN1B is associated with febrile seizures and early onset absence epilepsy. Neurology 61(6): 854–856.

Baulac S, Huberfeld G, Gourfinkel‐An I et al. (2001) First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2‐subunit gene. Nature Genetics 28(1): 46–48.

Baulac S, Gourfinkel‐An I, Picard F et al. (1999) A second locus for familial generalized epilepsy with febrile seizures plus maps to chromosome 2q21‐q33. American Journal of Human Genetics 65(4): 1078–1085.

Biervert C, Schroeder BC, Kubisch C et al. (1998) A potassium channel mutation in neonatal human epilepsy. Science 279(5349): 403–406.

Charlier C, Singh NA, Ryan SG et al. (1998) A pore mutation in a novel KQT‐like potassium channel gene in an idiopathic epilepsy family. Nature Genetics 18(1): 53–55.

Chen Y, Lu J, Pan H et al. (2003) Association between genetic variation of CACNA1H and childhood absence epilepsy. Annals of Neurology 54(2): 239–243.

Cho YW, Motamedi GK, Laufenberg I et al. (2003) A Korean kindred with autosomal dominant nocturnal frontal lobe epilepsy and mental retardation. Archives of Neurology 60(11): 1625–1632.

Cossette P, Liu L, Brisebois K et al. (2002) Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nature Genetics 31(2): 184–189.

De FM, Becchetti A, Patrignani A et al. (2000) The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy. Nature Genetics 26(3): 275–276.

Dibbens LM, Feng HJ, Richards MC et al. (2004) GABRD encoding a protein for extra‐ or peri‐synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Human Molecular Genetics 13(13): 1315–1319.

Dibbens LM, Mullen S, Helbig I et al. (2009) Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance. Human Molecular Genetics 18(19): 3626–3631.

Escayg A, MacDonald BT, Meisler MH et al. (2000) Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nature Genetics 24(4): 343–345.

Escayg A, Heils A, MacDonald BT et al. (2001) A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus and prevalence of variants in patients with epilepsy. American Journal of Human Genetics 68(4): 866–873.

Fendri‐Kriaa N, Kammoun F, Rebai A et al. (2009) Genetic screening of two Tunisian families with generalized epilepsy with febrile seizures plus. European Journal of Neurology 16(6): 697–704.

Harkin LA, Bowser DN, Dibbens LM et al. (2002) Truncation of the GABA(A)‐receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus. American Journal of Human Genetics 70(2): 530–536.

Hauser WA, Annegers JF and Rocca WA (1996) Descriptive epidemiology of epilepsy: contributions of population‐based studies from Rochester, Minnesota. Mayo Clinic Proceedings 71(6): 576–586.

Heron SE, Khosravani H, Varela D et al. (2007) Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants. Annals of Neurology 62(6): 560–568.

Hirose S, Iwata H, Akiyoshi H et al. (1999) A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy. Neurology 53(8): 1749–1753.

Kananura C, Haug K, Sander T et al. (2002) A splice‐site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions. Archives of Neurology 59(7): 1137–1141.

Kapoor A, Satishchandra P, Ratnapriya R et al. (2008) An idiopathic epilepsy syndrome linked to 3q13.3‐q21 and missense mutations in the extracellular calcium sensing receptor gene. Annals of Neurology 64(2): 158–167.

Leppert M, Anderson E, Quattlebaum T et al. (1989) Benign familial neonatal convulsions linked to genetic markers on chromosome 20. Nature 337(6208): 647–648.

Lewis TB, Leach RJ, Ward K, O'Connell P and Ryan SG (1993) Genetic heterogeneity in benign familial neonatal convulsions: identification of a new locus on chromosome 8q. American Journal of Human Genetics 53(3): 670–675.

Lossin C, Rhodes TH, Desai RR et al. (2003) Epilepsy‐associated dysfunction in the voltage‐gated neuronal sodium channel SCN1A. Journal of Neuroscience 23(36): 11289–11295.

Ma S, Blair MA, bou‐Khalil B et al. (2006) Mutations in the GABRA1 and EFHC1 genes are rare in familial juvenile myoclonic epilepsy. Epilepsy Research 71(2–3): 129–134.

Medina MT, Suzuki T, Alonso ME et al. (2008) Novel mutations in Myoclonin1/EFHC1 in sporadic and familial juvenile myoclonic epilepsy. Neurology 70(22 Pt 2): 2137–2144.

Miraglia del GE, Coppola G, Scuccimarra G et al. (2000) Benign familial neonatal convulsions (BFNC) resulting from mutation of the KCNQ2 voltage sensor. European Journal of Human Genetics 8(12): 994–997.

Moulard B, Guipponi M, Chaigne D et al. (1999) Identification of a new locus for generalized epilepsy with febrile seizures plus (GEFS+) on chromosome 2q24‐q33. American Journal of Human Genetics 65(5): 1396–1400.

Orrico A, Galli L, Grosso S et al. (2009) Mutational analysis of the SCN1A, SCN1B and GABRG2 genes in 150 Italian patients with idiopathic childhood epilepsies. Clinical Genetics 75(6): 579–581.

Phillips HA, Favre I, Kirkpatrick M et al. (2001) CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy. American Journal of Human Genetics 68(1): 225–231.

Phillips HA, Scheffer IE, Berkovic SF et al. (1995) Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q 13.2. Nature Genetics 10(1): 117–118.

Saenz A, Galan J, Caloustian C et al. (1999) Autosomal dominant nocturnal frontal lobe epilepsy in a Spanish family with a Ser252Phe mutation in the CHRNA4 gene. Archives of Neurology 56(8): 1004–1009.

Sander T, Schulz H, Saar K et al. (2000) Genome search for susceptibility loci of common idiopathic generalised epilepsies. Human Molecular Genetics 9(10): 1465–1472.

Singh NA, Pappas C, Dahle EJ et al. (2009) A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome. PLoS Genetics 5(9): e1000649.

Singh NA, Westenskow P, Charlier C et al. (2003) KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. Brain 126(Pt 12): 2726–2737.

Singh R, Andermann E, Whitehouse WP et al. (2001) Severe myoclonic epilepsy of infancy: extended spectrum of GEFS+? Epilepsia 42(7): 837–844.

Steinlein OK, Magnusson A, Stoodt J et al. (1997) An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy. Human Molecular Genetics 6(6): 943–947.

Steinlein OK, Mulley JC, Propping P et al. (1995) A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nature Genetics 11(2): 201–203.

Stogmann E, Lichtner P, Baumgartner C et al. (2006) Idiopathic generalized epilepsy phenotypes associated with different EFHC1 mutations. Neurology 67(11): 2029–2031.

Sugawara T, Mazaki‐Miyazaki E, Ito M et al. (2001) Nav1.1 mutations cause febrile seizures associated with afebrile partial seizures. Neurology 57(4): 703–705.

Suzuki T, Delgado‐Escueta AV, Aguan K et al. (2004) Mutations in EFHC1 cause juvenile myoclonic epilepsy. Nature Genetics 36(8): 842–849.

Suzuki T, Miyamoto H, Nakahari T et al. (2009) Efhc1 deficiency causes spontaneous myoclonus and increased seizure susceptibility. Human Molecular Genetics 18(6): 1099–1109.

Tanaka M, Olsen RW, Medina MT et al. (2008) Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy. American Journal of Human Genetics 82(6): 1249–1261.

Urak L, Feucht M, Fathi N, Hornik K and Fuchs K (2006) A GABRB3 promoter haplotype associated with childhood absence epilepsy impairs transcriptional activity. Human Molecular Genetics 15(16): 2533–2541.

Wallace RH, Wang DW, Singh R et al. (1998) Febrile seizures and generalized epilepsy associated with a mutation in the Na+‐channel beta1 subunit gene SCN1B. Nature Genetics 19(4): 366–370.

Wallace RH, Marini C, Petrou S et al. (2001a) Mutant GABA(A) receptor gamma2‐subunit in childhood absence epilepsy and febrile seizures. Nature Genetics 28(1): 49–52.

Wallace RH, Scheffer IE, Barnett S et al. (2001b) Neuronal sodium‐channel alpha1‐subunit mutations in generalized epilepsy with febrile seizures plus. American Journal of Human Genetics 68(4): 859–865.

Zimprich F, Ronen GM, Stogmann W et al. (2006) Andreas Rett and benign familial neonatal convulsions revisited. Neurology 67(5): 864–866.

Further Reading

Ashcroft F (1999) Ion Channels and Disease, 1st edn. London: Academic Press.

Berg AT, Berkovic SF, Brodie MJ 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): 676–685.

Cossette P (2010) Channelopathies and juvenile myoclonic epilepsy. Epilepsia 51(suppl. 1): 30–32.

International SNP Map Working Group (2001) A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 409(6822): 928–933.

Lerche H, Jurkat‐Rott K and Lehmann‐Horn F (2001) Ion channels and epilepsy. American Journal of Medical Genetics 106: 146–159.

Robinson R and Gardiner RM (2004) Molecular basis of Mendelian idiopathic epilepsies. Annals of Medicine 36(2): 89–97.

Scheffer IE and Berkovic SF (2010) Copy number variants – an unexpected risk factor for the idiopathic generalized epilepsies. Brain 133(1): 7–8.

Scheffer IE, Zhang YH, Gecz J and Dibbens L (2010) Genetics of the epilepsies: genetic twists in the channels and other tales. Epilepsia 51(suppl. 1): 33–36.

Steinlein OK and Noebels JL (2000) Ion channels and epilepsy in man and mouse. Current Opinion in Genetics and Development 10: 286–291.

Tan NC and Berkovic SF (2010) The Epilepsy Genetic Association Database (epiGAD): analysis of 165 genetic association studies, 1996–2008. Epilepsia 51(4): 686–689.

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Everett, Kate V(Oct 2010) Epilepsy: Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005568.pub2]