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Semin Neurol 2020; 40(06): 730-738
DOI: 10.1055/s-0040-1719070
Review Article

Genetic Testing in Epilepsy

David M. Ritter 
1   Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
2   Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
,
Katherine Holland
1   Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
2   Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
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Abstract

Because of next-generation sequencing and the discovery of many new causative genes, genetic testing in epilepsy patients has become widespread. Pathologic variants resulting in epilepsy cause a variety of changes that can be broadly classified into syndromic disorders (i.e., chromosomal abnormalities), metabolic disorders, brain malformations, and abnormal cellular signaling. Here, we review the available genetic testing, reasons to pursue genetic testing, common genetic causes of epilepsy, the data behind what patients are found to have genetic epilepsies based on current testing, and discussing these results with patients. We propose an algorithm for testing patients with epilepsy to maximize yield and limit costs based on their phenotype (including electroencephalography and magnetic resonance imaging findings), age of seizure onset, and presence of other neurologic comorbidities. Being able to discern which type of genetic testing to order, using that information to give targeted and cost-effective patient care, and interpreting results accurately will be a crucial skill for the modern neurologist.

Keywords

epilepsy - genetics - genetic testing


Publikationsverlauf

Artikel online veröffentlicht:
11. November 2020

© 2020. Thieme. All rights reserved.

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  • References

  • 1 Myers KA, Johnstone DL, Dyment DA. Epilepsy genetics: current knowledge, applications, and future directions. Clin Genet 2019; 95 (01) 95-111
    CrossrefPubMedGoogle Scholar
  • 2 Allen AS, Berkovic SF, Cossette P. Epi4K Consortium, Epilepsy Phenome/Genome Project. et al. De novo mutations in epileptic encephalopathies. Nature 2013; 501 (7466): 217-221
    Google Scholar
  • 3 Tran Mau-Them F, Guibaud L, Duplomb L. et al. De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy. Genet Med 2019; 21 (04) 1008-1014
    CrossrefPubMedGoogle Scholar
  • 4 Yap SM, Smyth S. Ryanodine receptor 2 (RYR2) mutation: a potentially novel neurocardiac calcium channelopathy manifesting as primary generalised epilepsy. Seizure 2019; 67: 11-14
    CrossrefPubMedGoogle Scholar
  • 5 Axeen EJT, Olson HE. Neonatal epilepsy genetics. Semin Fetal Neonatal Med 2018; 23 (03) 197-203
    CrossrefPubMedGoogle Scholar
  • 6 Perucca P, Perucca E. Identifying mutations in epilepsy genes: impact on treatment selection. Epilepsy Res 2019; 152: 18-30
    CrossrefPubMedGoogle Scholar
  • 7 McTague A, Howell KB, Cross JH, Kurian MA, Scheffer IE. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol 2016; 15 (03) 304-316
    Google Scholar
  • 8 Mouro FM, Miranda-Lourenço C, Sebastião AM, Diógenes MJ. From cannabinoids and neurosteroids to statins and the ketogenic diet: new therapeutic avenues in Rett syndrome?. Front Neurosci 2019; 13: 680
    CrossrefPubMedGoogle Scholar
  • 9 Steel D, Symonds JD, Zuberi SM, Brunklaus A. Dravet syndrome and its mimics: beyond SCN1A. Epilepsia 2017; 58 (11) 1807-1816
    CrossrefPubMedGoogle Scholar
  • 10 Oyrer J, Maljevic S, Scheffer IE, Berkovic SF, Petrou S, Reid CA. Ion channels in genetic epilepsy: from genes and mechanisms to disease-targeted therapies. Pharmacol Rev 2018; 70 (01) 142-173
    CrossrefPubMedGoogle Scholar
  • 11 Devinsky O, Cross JH, Laux L. Cannabidiol in Dravet Syndrome Study Group. et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med 2017; 376 (21) 2011-2020
    CrossrefPubMedGoogle Scholar
  • 12 Wirrell EC, Laux L, Franz DN. et al. Stiripentol in Dravet syndrome: results of a retrospective U.S. study. Epilepsia 2013; 54 (09) 1595-1604
    CrossrefPubMedGoogle Scholar
  • 13 Schubert-Bast S, Hofstetter P, Fischer D, Schloesser R, Ramantani G, Kieslich M. Sodium channel blockers in KCNQ2-encephalopathy: Lacosamide as a new treatment option. Seizure 2017; 51: 171-173
    CrossrefPubMedGoogle Scholar
  • 14 Stamberger H, Nikanorova M, Willemsen MH. et al. STXBP1 encephalopathy: a neurodevelopmental disorder including epilepsy. Neurology 2016; 86 (10) 954-962
    CrossrefPubMedGoogle Scholar
  • 15 Vlaskamp DRM, Shaw BJ, Burgess R. et al. SYNGAP1 encephalopathy: a distinctive generalized developmental and epileptic encephalopathy. Neurology 2019; 92 (02) e96-e107
    CrossrefPubMedGoogle Scholar
  • 16 Koch H, Weber YG. The glucose transporter type 1 (Glut1) syndromes. Epilepsy Behav 2019; 91: 90-93
    CrossrefPubMedGoogle Scholar
  • 17 Larsen J, Johannesen KM, Ek J. MAE working group of EuroEPINOMICS RES Consortium. et al. The role of SLC2A1 mutations in myoclonic astatic epilepsy and absence epilepsy, and the estimated frequency of GLUT1 deficiency syndrome. Epilepsia 2015; 56 (12) e203-e208
    CrossrefPubMedGoogle Scholar
  • 18 Klepper J, Scheffer H, Leiendecker B. et al. Seizure control and acceptance of the ketogenic diet in GLUT1 deficiency syndrome: a 2- to 5-year follow-up of 15 children enrolled prospectively. Neuropediatrics 2005; 36 (05) 302-308
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 19 Ream MA, Patel AD. Obtaining genetic testing in pediatric epilepsy. Epilepsia 2015; 56 (10) 1505-1514
    CrossrefPubMedGoogle Scholar
  • 20 Tekgul H, Serdaroğlu G, Karapinar B. et al. Vigabatrin caused rapidly progressive deterioration in two cases with early myoclonic encephalopathy associated with nonketotic hyperglycinemia. J Child Neurol 2006; 21 (01) 82-84
    CrossrefPubMedGoogle Scholar
  • 21 Bjoraker KJ, Swanson MA, Coughlin II CR. et al. Neurodevelopmental outcome and treatment efficacy of benzoate and dextromethorphan in siblings with attenuated nonketotic hyperglycinemia. J Pediatr 2016; 170: 234-239
    CrossrefPubMedGoogle Scholar
  • 22 Mills PB, Camuzeaux SSM, Footitt EJ. et al. Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome. Brain 2014; 137 (Pt 5): 1350-1360
    CrossrefPubMedGoogle Scholar
  • 23 van Karnebeek CDM, Tiebout SA, Niermeijer J. et al. Pyridoxine-dependent epilepsy: an expanding clinical spectrum. Pediatr Neurol 2016; 59: 6-12
    Google Scholar
  • 24 van Karnebeek CDM, Sayson B, Lee JJY. et al. Metabolic evaluation of epilepsy: a diagnostic algorithm with focus on treatable conditions. Front Neurol 2018; 9: 1016
    Google Scholar
  • 25 Williams RE, Adams HR, Blohm M. et al. Management strategies for CLN2 disease. Pediatr Neurol 2017; 69: 102-112
    CrossrefPubMedGoogle Scholar
  • 26 Johnson TB, Cain JT, White KA, Ramirez-Montealegre D, Pearce DA, Weimer JM. Therapeutic landscape for Batten disease: current treatments and future prospects. Nat Rev Neurol 2019; 15 (03) 161-178
    CrossrefPubMedGoogle Scholar
  • 27 Ye Z, McQuillan L, Poduri A. et al. Somatic mutation: the hidden genetics of brain malformations and focal epilepsies. Epilepsy Res 2019; 155: 106161
    CrossrefPubMedGoogle Scholar
  • 28 Krueger DA, Northrup H. International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013; 49 (04) 255-265
    CrossrefPubMedGoogle Scholar
  • 29 Lechuga L, Franz DN. Everolimus as adjunctive therapy for tuberous sclerosis complex-associated partial-onset seizures. Expert Rev Neurother 2019; 19 (10) 913-925
    CrossrefPubMedGoogle Scholar
  • 30 Baldassari S, Picard F, Verbeek NE. et al. The landscape of epilepsy-related GATOR1 variants. Genet Med 2019; 21 (02) 398-408
    Google Scholar
  • 31 Loddenkemper T, Holland KD, Stanford LD, Kotagal P, Bingaman W, Wyllie E. Developmental outcome after epilepsy surgery in infancy. Pediatrics 2007; 119 (05) 930-935
    CrossrefPubMedGoogle Scholar
  • 32 Meuwissen MEC, Halley DJJ, Smit LS. et al. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Genet Med 2015; 17 (11) 843-853
    Google Scholar
  • 33 Al Mutairi F, Alfadhel M, Nashabat M. et al. Phenotypic and molecular spectrum of Aicardi-Goutières syndrome: a study of 24 patients. Pediatr Neurol 2018; 78: 35-40
    CrossrefPubMedGoogle Scholar
  • 34 Danti FR, Galosi S, Romani M. et al. GNAO1 encephalopathy: broadening the phenotype and evaluating treatment and outcome. Neurol Genet 2017; 3 (02) e143
    CrossrefPubMedGoogle Scholar
  • 35 Demarest ST, Olson HE, Moss A. et al. CDKL5 deficiency disorder: relationship between genotype, epilepsy, cortical visual impairment, and development. Epilepsia 2019; 60 (08) 1733-1742
    CrossrefPubMedGoogle Scholar
  • 36 Lee JH, Huynh M, Silhavy JL. et al. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat Genet 2012; 44 (08) 941-945
    Google Scholar
  • 37 Srivastava S, Olson HE, Cohen JS. et al. BRAT1 mutations present with a spectrum of clinical severity. Am J Med Genet A 2016; 170 (09) 2265-2273
    CrossrefPubMedGoogle Scholar
  • 38 Horn D, Weschke B, Knierim E. et al. BRAT1 mutations are associated with infantile epileptic encephalopathy, mitochondrial dysfunction, and survival into childhood. Am J Med Genet A 2016; 170 (09) 2274-2281
    CrossrefPubMedGoogle Scholar
  • 39 Chen H, Qian Y, Yu S. et al. Early onset developmental delay and epilepsy in pediatric patients with WDR45 variants. Eur J Med Genet 2019; 62 (02) 149-160
    CrossrefPubMedGoogle Scholar
  • 40 Lindy AS, Stosser MB, Butler E. et al. Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. Epilepsia 2018; 59 (05) 1062-1071
    CrossrefPubMedGoogle Scholar
  • 41 Butler KM, da Silva C, Alexander JJ, Hegde M, Escayg A. Diagnostic yield from 339 epilepsy patients screened on a clinical gene panel. Pediatr Neurol 2017; 77: 61-66
    CrossrefPubMedGoogle Scholar
  • 42 Perucca P, Scheffer IE, Harvey AS. et al. Real-world utility of whole exome sequencing with targeted gene analysis for focal epilepsy. Epilepsy Res 2017; 131: 1-8
    CrossrefPubMedGoogle Scholar
  • 43 Helbig KL, Farwell Hagman KD, Shinde DN. et al. Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet Med 2016; 18 (09) 898-905
    CrossrefPubMedGoogle Scholar
  • 44 Demos M, Guella I, DeGuzman C. et al. Diagnostic yield and treatment impact of targeted exome sequencing in early-onset epilepsy. Front Neurol 2019; 10: 434
    CrossrefPubMedGoogle Scholar
  • 45 Mercimek-Mahmutoglu S, Patel J, Cordeiro D. et al. Diagnostic yield of genetic testing in epileptic encephalopathy in childhood. Epilepsia 2015; 56 (05) 707-716
    CrossrefPubMedGoogle Scholar
  • 46 Peng J, Pang N, Wang Y. et al. Next-generation sequencing improves treatment efficacy and reduces hospitalization in children with drug-resistant epilepsy. CNS Neurosci Ther 2019; 25 (01) 14-20
    CrossrefPubMedGoogle Scholar
  • 47 Ortega-Moreno L, Giráldez BG, Soto-Insuga V. Grupo Español de Genética de las Epilepsias de la Infancia (GEGEI). et al. Molecular diagnosis of patients with epilepsy and developmental delay using a customized panel of epilepsy genes. PLoS One 2017; 12 (11) e0188978
    Google Scholar
  • 48 Papuc SM, Abela L, Steindl K. et al. The role of recessive inheritance in early-onset epileptic encephalopathies: a combined whole-exome sequencing and copy number study. Eur J Hum Genet 2019; 27 (03) 408-421
    CrossrefPubMedGoogle Scholar
  • 49 Berg AT, Coryell J, Saneto RP. et al. Early-life epilepsies and the emerging role of genetic testing. JAMA Pediatr 2017; 171 (09) 863-871
    CrossrefPubMedGoogle Scholar
  • 50 Trump N, McTague A, Brittain H. et al. Improving diagnosis and broadening the phenotypes in early-onset seizure and severe developmental delay disorders through gene panel analysis. J Med Genet 2016; 53 (05) 310-317
    CrossrefPubMedGoogle Scholar
  • 51 Yang L, Kong Y, Dong X. et al. Clinical and genetic spectrum of a large cohort of children with epilepsy in China. Genet Med 2019; 21 (03) 564-571
    CrossrefPubMedGoogle Scholar
  • 52 Howell KB, Eggers S, Dalziel K. Victorian Severe Epilepsy of Infancy Study Group. et al. A population-based cost-effectiveness study of early genetic testing in severe epilepsies of infancy. Epilepsia 2018; 59 (06) 1177-1187
    CrossrefPubMedGoogle Scholar
  • 53 Shellhaas RA, Wusthoff CJ, Tsuchida TN. Neonatal Seizure Registry. et al. Profile of neonatal epilepsies: characteristics of a prospective US cohort. Neurology 2017; 89 (09) 893-899
    CrossrefPubMedGoogle Scholar
  • 54 Bruun TUJ, DesRoches CL, Wilson D. et al. Prospective cohort study for identification of underlying genetic causes in neonatal encephalopathy using whole-exome sequencing. Genet Med 2018; 20 (05) 486-494
    CrossrefPubMedGoogle Scholar
  • 55 Muona M, Berkovic SF, Dibbens LM. et al. A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nat Genet 2015; 47 (01) 39-46
    CrossrefPubMedGoogle Scholar
  • 56 Angione K, Eschbach K, Smith G, Joshi C, Demarest S. Genetic testing in a cohort of patients with potential epilepsy with myoclonic-atonic seizures. Epilepsy Res 2019; 150: 70-77
    CrossrefPubMedGoogle Scholar
  • 57 Oates S, Tang S, Rosch R. et al. Incorporating epilepsy genetics into clinical practice: a 360°evaluation. NPJ Genom Med 2018; 3: 13
    Google Scholar
  • 58 Jaitovich Groisman I, Hurlimann T, Godard B. Parents of a child with epilepsy: views and expectations on receiving genetic results from whole genome sequencing. Epilepsy Behav 2019; 90: 178-190
    CrossrefPubMedGoogle Scholar
  • 59 Stevelink R, Sanders MWCB, Tuinman MP. et al. Epilepsy surgery for patients with genetic refractory epilepsy: a systematic review. Epileptic Disord 2018; 20 (02) 99-115
    CrossrefPubMedGoogle Scholar
  • 60 Sánchez Fernández I, Loddenkemper T, Gaínza-Lein M, Sheidley BR, Poduri A. Diagnostic yield of genetic tests in epilepsy: a meta-analysis and cost-effectiveness study. Neurology 2019; 92: E418-E428
    CrossrefPubMedGoogle Scholar
  • 61 Wofford S, Noblin S, Davis JM. et al. Genetic testing practices of genetic counselors, geneticists, and pediatric neurologists with regard to childhood-onset neurogenetic conditions. J Child Neurol 2019; 34: 177-183
    CrossrefPubMedGoogle Scholar
  • 62 Tsai MH, Chan CK, Chang YC. et al. Molecular genetic characterization of patients with focal epilepsy using a customized targeted resequencing gene panel. Front Neurol 2018; 9: 515
    Google Scholar
  • 63 Jain P, Andrade D, Donner E. et al. Development of criteria for epilepsy genetic testing in Ontario, Canada. Can J Neurol Sci 2019; 46 (01) 7-13
    CrossrefPubMedGoogle Scholar
  • 64 Mullen SA, Berkovic SF. ILAE Genetics Commission. Genetic generalized epilepsies. Epilepsia 2018; 59 (06) 1148-1153
    CrossrefPubMedGoogle Scholar
  • 65 Orsini A, Zara F, Striano P. Recent advances in epilepsy genetics. Neurosci Lett 2018; 667: 4-9
    CrossrefPubMedGoogle Scholar
  • 66 Patel J, Mercimek-Mahmutoglu S. Epileptic encephalopathy in childhood: a stepwise approach for identification of underlying genetic causes. Indian J Pediatr 2016; 83 (10) 1164-1174
    CrossrefPubMedGoogle Scholar
  • 67 Chen P, Lin J-J, Lu C-S. Taiwan SJS Consortium. et al. Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. N Engl J Med 2011; 364 (12) 1126-1133
    CrossrefPubMedGoogle Scholar
  • 68 McCormack M, Alfirevic A, Bourgeois S. et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med 2011; 364 (12) 1134-1143
    CrossrefPubMedGoogle Scholar
  • 69 Hamdan FF, Myers CT, Cossette P. Deciphering Developmental Disorders Study. et al. High rate of recurrent de novo mutations in developmental and epileptic encephalopathies. Am J Hum Genet 2017; 101 (05) 664-685
    CrossrefPubMedGoogle Scholar