Monogenic Epilepsies in Adult Epilepsy Clinics and Gene-Driven Approaches to Treatment

Ellis CA, Petrovski S, Berkovic SF. Epilepsy genetics: clinical impacts and biological insights. Lancet Neurol. 2020;19:93–100.

Article  CAS  PubMed  Google Scholar 

Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58:512–21.

Article  PubMed  PubMed Central  Google Scholar 

Oliver KL, Scheffer IE, Ellis CA, Grinton BE, Epi4K Consortium, Berkovic SF, et al. Investigating the effect of polygenic background on epilepsy phenotype in “monogenic” families. EBioMedicine. 2024;109:105404. https://doi.org/10.1016/j.ebiom.2024.105404

Martins Custodio H, Clayton LM, Bellampalli R, Pagni S, Silvennoinen K, Caswell R, et al. Widespread genomic influences on phenotype in Dravet syndrome, a “monogenic” condition. Brain [Internet]. 2023; Available from: https://doi.org/10.1093/brain/awad111

Lai D, Gade M, Yang E, Koh HY, Lu J, Walley NM, et al. Somatic variants in diverse genes leads to a spectrum of focal cortical malformations. Brain. 2022;145:2704–20.

Article  PubMed  PubMed Central  Google Scholar 

Steinlein OK, Mulley JC, Propping P, Wallace RH, Phillips HA, Sutherland GR, et al. A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet. 1995;11:201–3.

Article  CAS  PubMed  Google Scholar 

Epicure Consortium, Leu C, de Kovel CG, Zara F, Striano P, Pezzella M, Robbiano A, Bianchi A, Bisulli F, Coppola A, Giallonardo AT. Genome‐wide linkage meta‐analysis identifies susceptibility loci at 2q34 and 13q31. 3 for genetic generalized epilepsies. Epilepsia. 2012 Feb;53(2):308-18.

International League Against Epilepsy Consortium on Complex Epilepsies. Electronic address: epilepsy-austin@unimelb.edu.au. Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. Lancet Neurol. 2014;13:893–903.

International League Against Epilepsy Consortium on Complex Epilepsies. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat Commun. 2018;9:5269.

Article  Google Scholar 

Berkovic SF, Howell RA, Hay DA, Hopper JL. Epilepsies in twins: genetics of the major epilepsy syndromes. Ann Neurol. 1998;43:435–45.

Article  CAS  PubMed  Google Scholar 

International League Against Epilepsy Consortium on Complex Epilepsies, Samuel F Berkovic, Gianpiero L Cavalleri, Bobby PC Koeleman. Genome-wide meta-analysis of over 29,000 people with epilepsy reveals 26 loci and subtype-specific genetic architecture. medRxiv [Internet]. 2022; Available from: https://doi.org/10.1101/2022.06.08.22276120

Oliver KL, Scheffer IE, Bennett MF, Grinton BE, Bahlo M, Berkovic SF. Genes4Epilepsy: An epilepsy gene resource. Epilepsia. 2023;64:1368–75.

Article  PubMed  PubMed Central  Google Scholar 

Macnee M, Pérez-Palma E, López-Rivera JA, Ivaniuk A, May P, Møller RS, et al. Data-driven historical characterization of epilepsy-associated genes. Eur J Paediatr Neurol. 2023;42:82–7.

Article  CAS  PubMed  Google Scholar 

Zhang M-W, Liang X-Y, Wang J, Gao L-D, Liao H-J, He Y-H, et al. Epilepsy-associated genes: an update. Seizure. 2024;116:4–13.

Article  PubMed  Google Scholar 

Xian J, Helbig I. Guardians of the epilepsy genome. Eur J Paediat Neurol. 2023;1(42):A4-6.

Article  Google Scholar 

Helbig I, Riggs ER, Barry C-A, Klein KM, Dyment D, Thaxton C, et al. The ClinGen Epilepsy Gene Curation Expert Panel-Bridging the divide between clinical domain knowledge and formal gene curation criteria. Hum Mutat. 2018;39:1476–84.

Article  PubMed  Google Scholar 

Stark Z, Foulger RE, Williams E, Thompson BA, Patel C, Lunke S, et al. Scaling national and international improvement in virtual gene panel curation via a collaborative approach to discordance resolution. Am J Hum Genet. 2021;108:1551–7.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Epi4K Consortium, Epilepsy Phenome/Genome Project, Allen AS, Berkovic SF, Cossette P, Delanty N, et al. De novo mutations in epileptic encephalopathies. Nature. 2013;501:217–21. https://doi.org/10.1038/nature12439

Hamdan FF, Myers CT, Cossette P, Lemay P, Spiegelman D, Laporte AD, et al. High rate of recurrent DE Novo mutations in developmental and epileptic encephalopathies. Am J Hum Genet. 2017;101:664–85.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet. 2001;68:1327–32.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lewis-Smith D, Ellis CA, Helbig I, Thomas RH. Early-onset genetic epilepsies reaching adult clinics. Brain. 2020;143(3):e19.

Article  PubMed  PubMed Central  Google Scholar 

Catarino CB, Liu JYW, Liagkouras I, Gibbons VS, Labrum RW, Ellis R, et al. Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology. Brain. 2011;134:2982–3010.

Article  PubMed  PubMed Central  Google Scholar 

Silvennoinen K, Puvirajasinghe C, Hudgell K, Sidhu MK, Martins Custodio H, Genomics England Research Consortium, et al. Late diagnoses of Dravet syndrome: How many individuals are we missing? Epilepsia Open [Internet]. 2021; Available from: https://doi.org/10.1002/epi4.12525

Vakrinou A, Pagni S, Mills JD, Clayton LM, Balestrini S, Sisodiya SM. Adult phenotypes of genetic developmental and epileptic encephalopathies. Brain Communications. 2025;7(1):fcaf028.

Hirsch E, French J, Scheffer IE, Bogacz A, Alsaadi T, Sperling MR, et al. ILAE definition of the idiopathic generalized epilepsy syndromes: Position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022;63:1475–99.

Article  PubMed  Google Scholar 

International League Against Epilepsy Consortium on Complex Epilepsies. GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture. Nat Genet. 2023;55:1471–82.

Article  CAS  Google Scholar 

Epi4K consortium, Epilepsy Phenome/Genome Project. Ultra-rare genetic variation in common epilepsies: a case-control sequencing study. Lancet Neurol. 2017;16:135–43.

May P, Girard S, Harrer M, Bobbili DR, Schubert J, Wolking S, et al. Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study. Lancet Neurol. 2018;17:699–708.

Article  CAS  PubMed  Google Scholar 

Jallon P, Latour P. Epidemiology of idiopathic generalized epilepsies. Epilepsia. 2005;46(Suppl 9):10–4.

Article  PubMed  Google Scholar 

Weber YG, Lerche H. Genetic mechanisms in idiopathic epilepsies. Dev Med Child Neurol. 2008;50:648–54.

Article  PubMed  Google Scholar 

Cossette P, Liu L, Brisebois K, Dong H, Lortie A, Vanasse M, et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet. 2002;31:184–9.

Article  CAS  PubMed  Google Scholar 

Wallace RH, Marini C, Petrou S, Harkin LA, Bowser DN, Panchal RG, et al. Mutant GABAA receptor γ2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet. 2001;28:49–52.

Article  CAS  PubMed  Google Scholar 

Arsov T, Mullen SA, Rogers S, Phillips AM, Lawrence KM, Damiano JA, et al. Glucose transporter 1 deficiency in the idiopathic generalized epilepsies. Ann Neurol. 2012;72:807–15.

Article  CAS  PubMed  Google Scholar 

Johannesen K, Marini C, Pfeffer S, Møller RS, Dorn T, Niturad CE, et al. Phenotypic spectrum of GABRA1: From generalized epilepsies to severe epileptic encephalopathies. Neurology. 2016;87:1140–51.

Article  CAS  PubMed  Google Scholar 

Leen WG, Klepper J, Verbeek MM, Leferink M, Hofste T, van Engelen BG, et al. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain. 2010;133:655–70.

Article  PubMed  Google Scholar 

Kang J-Q, Macdonald RL. Molecular pathogenic basis for GABRG2 mutations associated with a spectrum of epilepsy syndromes, from generalized absence epilepsy to Dravet syndrome. JAMA Neurol. 2016;73:1009–16.

Article  PubMed  PubMed Central  Google Scholar 

Helbig I, Hartmann C, Mefford HC. The unexpected role of copy number variations in juvenile myoclonic epilepsy. Epilepsy Behav. 2013;28(Suppl 1):S66–8.

Article  PubMed  Google Scholar 

Helbig I, Mefford HC, Sharp AJ, Guipponi M, Fichera M, Franke A, Muhle H, De Kovel C, Baker C, Von Spiczak S. Kron KL 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nature Genet. 2009;41(2):160–2.

Article  CAS  PubMed  Google Scholar 

de Kovel CG, Trucks H, Helbig I, Mefford HC, Baker C, Leu C, Kluck C, Muhle H, von Spiczak S, Ostertag P, Obermeier T. Recurrent microdeletions at 15q112 and 16p1311 predispose to idiopathic generalized epilepsies. Brain. 2010;133(1):23–32.

Article  PubMed 

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