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Genetics of Epilepsy in the Era of Precision Medicine: Implications for Testing, Treatment, and Genetic Counseling

  • Genetic Counseling and Clinical Testing (B LeRoy and N Callanan, Section Editors)
  • Published:
Current Genetic Medicine Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Epilepsy is among the most common neurological diseases, affecting 65 million people worldwide. Recent revisions to the classification of epilepsies by the International League Against Epilepsy (ILAE) reflect a growing awareness of genetic contributions to epilepsy. Research in epilepsy genetics has begun to look beyond gene discovery to the horizon of genotype-driven precision medicine.

Recent Findings

During the past 5 years, the advent of next-generation sequencing has led to exponential growth in the discovery of epilepsy-related genes. The yield of clinically available genetic tests for patients with epilepsy may be as high as 50%, particularly among patients with early-onset epileptic encephalopathy (EOEE). Among patients with early-life epilepsies who have a genetic diagnosis, de novo pathogenic variants are most frequently observed, and rates of somatic mosaicism among both patients and parents are higher than initially anticipated. Phenotypic heterogeneity is quite broad for many epilepsy-related genes, and genotype-phenotype correlations continue to prove complex and at times challenging.

Summary

With a focus on early-life epilepsies, we review recent highlights from the literature regarding gene discovery, approaches to and outcomes of clinical genetic evaluation, and contemporary efforts toward precision treatment. We also address genetic counseling issues of relevance for this population.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014;55(4):475–82.

    Article  PubMed  Google Scholar 

  2. Fisher RS, Cross JH, French JA, Higurashi N, Hirsch E, Jansen FE, et al. Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):522–30.

    Article  PubMed  Google Scholar 

  3. • 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(4):512–21. This paper describes the revised classification of epilepsy types, etiologies and syndromes, incorprated increased recognition of genetic contribution.

    Article  PubMed  PubMed Central  Google Scholar 

  4. 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(2):201–3.

    Article  PubMed  CAS  Google Scholar 

  5. •• Epi4K Consortium. Epi4K: gene discovery in 4,000 genomes. Epilepsia. 2012;53(8):1457–67. This paper describes the collaborative efforts of an NINDS-funded “Center Without Walls” focused on the genetics of epilepsy.

    Article  Google Scholar 

  6. • EPGP Collaborative, Abou-Khalil B, Alldredge B, Bautista J, Berkovic S, Bluvstein J, et al. The epilepsy phenome/genome project. Clin Trials. 2013;10(4):568–86. Describes the first large multi-center collaborative effort to gather phenotypic information from patients with epilepsy along with DNA for genotyping.

    Article  Google Scholar 

  7. •• EuroEPINOMICS-RES Consortium, Epilepsy Phenome/Genome Project, Epi4K Consortium. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet. 2014;95(4):360–70. This study describes a combined whole exome sequencing effort between the Epi4K study and their European counterparts, the EuroEPINOMICS-RES Consortium, the largest WES study of epileptic encephalopathies.

    Article  CAS  Google Scholar 

  8. El Achkar CM, Olson HE, Poduri A, Pearl PL. The genetics of the epilepsies. Curr Neurol Neurosci Rep. 2015;15(7):39.

    Article  PubMed  CAS  Google Scholar 

  9. Scheffer IE. Epilepsy genetics revolutionizes clinical practice. Neuropediatrics. 2014;45(2):70–4.

    Article  PubMed  Google Scholar 

  10. Thomas RH, Berkovic SF. The hidden genetics of epilepsy—a clinically important new paradigm. Nat Rev Neurol. 2014;10(5):283–92.

    Article  PubMed  Google Scholar 

  11. Pandolfo M. Pediatric epilepsy genetics. Curr Opin Neurol. 2013;26(2):137–45.

    Article  PubMed  CAS  Google Scholar 

  12. 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(3):304–16.

    Article  PubMed  Google Scholar 

  13. Helbig I, Lowenstein DH. Genetics of the epilepsies: where are we and where are we going? Curr Opin Neurol. 2013;26(2):179–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. 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(7466):217–21.

    Article  CAS  Google Scholar 

  15. Epi4K Consortium. De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies. Am J Hum Genet. 2016;99(2):287–98.

    Article  CAS  Google Scholar 

  16. Mefford HC, Yendle SC, Hsu C, Cook J, Geraghty E, McMahon JM, et al. Rare copy number variants are an important cause of epileptic encephalopathies. Ann Neurol. 2011;70(6):974–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Epilepsy Phenome/Genome Project, Epi4K Consortium. Copy number variant analysis from exome data in 349 patients with epileptic encephalopathy. Ann Neurol. 2015;78(2):323–8.

    Article  CAS  Google Scholar 

  18. Trump N, McTague A, Brittain H, Papandreou A, Meyer E, Ngoh A, 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(5):310–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Helbig KL, Farwell Hagman KD, Shinde DN, Mroske C, Powis Z, Li S, et al. Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet Med. 2016;18(9):898–905.

    Article  PubMed  CAS  Google Scholar 

  20. 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(1):142–73.

    Article  PubMed  Google Scholar 

  21. Bayat A, Hjalgrim H, Moller RS. The incidence of SCN1A-related Dravet syndrome in Denmark is 1:22,000: a population-based study from 2004 to 2009. Epilepsia. 2015;56(4):e36–9.

    Article  PubMed  CAS  Google Scholar 

  22. Wolff M, Johannesen KM, Hedrich UBS, Masnada S, Rubboli G, Gardella E, et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain. 2017;140(5):1316–36.

    Article  PubMed  Google Scholar 

  23. Meisler MH, Helman G, Hammer MF, Fureman BE, Gaillard WD, Goldin AL, et al. SCN8A encephalopathy: research progress and prospects. Epilepsia. 2016;57(7):1027–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Moller RS, Larsen LH, Johannesen KM, Talvik I, Talvik T, Vaher U, et al. Gene panel testing in epileptic encephalopathies and familial epilepsies. Mol Syndromol. 2016;7(4):210–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. 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;77:61–6.

    Article  PubMed  Google Scholar 

  26. Parrini E, Marini C, Mei D, Galuppi A, Cellini E, Pucatti D, et al. Diagnostic targeted resequencing in 349 patients with drug-resistant pediatric epilepsies identifies causative mutations in 30 different genes. Hum Mutat. 2017;38(2):216–25.

    Article  PubMed  CAS  Google Scholar 

  27. Millichap JJ, Park KL, Tsuchida T, Ben-Zeev B, Carmant L, Flamini R, et al. KCNQ2 encephalopathy: features, mutational hot spots, and ezogabine treatment of 11 patients. Neurol Genet. 2016;2(5):e96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Masnada S, Hedrich UBS, Gardella E, Schubert J, Kaiwar C, Klee EW, et al. Clinical spectrum and genotype-phenotype associations of KCNA2-related encephalopathies. Brain. 2017;140(9):2337–54.

    Article  PubMed  Google Scholar 

  29. de Kovel CGF, Syrbe S, Brilstra EH, Verbeek N, Kerr B, Dubbs H, et al. Neurodevelopmental disorders caused by de novo variants in KCNB1 genotypes and phenotypes. JAMA Neurol. 2017;74(10):1228–36.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Shellhaas RA, Wusthoff CJ, Tsuchida TN, Glass HC, Chu CJ, Massey SL, et al. Profile of neonatal epilepsies: characteristics of a prospective US cohort. Neurology. 2017;89(9):893–9.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Lesca G, Rudolf G, Bruneau N, Lozovaya N, Labalme A, Boutry-Kryza N, et al. GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nat Genet. 2013;45(9):1061–6.

    Article  PubMed  CAS  Google Scholar 

  32. Lemke JR, Lal D, Reinthaler EM, Steiner I, Nothnagel M, Alber M, et al. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet. 2013;45(9):1067–72.

    Article  PubMed  CAS  Google Scholar 

  33. Carvill GL, Regan BM, Yendle SC, O'Roak BJ, Lozovaya N, Bruneau N, et al. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet. 2013;45(9):1073–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Lemke JR, Geider K, Helbig KL, Heyne HO, Schutz H, Hentschel J, et al. Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy. Neurology. 2016;86(23):2171–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Platzer K, Yuan H, Schutz H, Winschel A, Chen W, Hu C, et al. GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects. J Med Genet. 2017;54(7):460–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Li D, Yuan H, Ortiz-Gonzalez XR, Marsh ED, Tian L, McCormick EM, et al. GRIN2D recurrent de novo dominant mutation causes a severe epileptic encephalopathy treatable with NMDA receptor channel blockers. Am J Hum Genet. 2016;99(4):802–16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Johannesen K, Marini C, Pfeffer S, Moller RS, Dorn T, Niturad CE, et al. Phenotypic spectrum of GABRA1: from generalized epilepsies to severe epileptic encephalopathies. Neurology. 2016;87(11):1140–51.

    Article  PubMed  CAS  Google Scholar 

  38. Shen D, Hernandez CC, Shen W, Hu N, Poduri A, Sheidley B, et al. De novo GABRG2 mutations associated with epileptic encephalopathies. Brain. 2017;140(1):49–67.

    Article  PubMed  Google Scholar 

  39. Moller RS, Wuttke TV, Helbig I, Marini C, Johannesen KM, Brilstra EH, et al. Mutations in GABRB3: from febrile seizures to epileptic encephalopathies. Neurology. 2017;88(5):483–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Rizo J, Xu J. The synaptic vesicle release machinery. Annu Rev Biophys. 2015;44:339–67.

    Article  PubMed  CAS  Google Scholar 

  41. Stamberger H, Nikanorova M, Willemsen MH, Accorsi P, Angriman M, Baier H, et al. STXBP1 encephalopathy: a neurodevelopmental disorder including epilepsy. Neurology. 2016;86(10):954–62.

    Article  PubMed  CAS  Google Scholar 

  42. Gburek-Augustat J, Beck-Woedl S, Tzschach A, Bauer P, Schoening M, Riess A. Epilepsy is not a mandatory feature of STXBP1 associated ataxia-tremor-retardation syndrome. Eur J Paediatr Neurol. 2016;20(4):661–5.

    Article  PubMed  Google Scholar 

  43. Suri M, Evers JMG, Laskowski RA, O'Brien S, Baker K, Clayton-Smith J, et al. Protein structure and phenotypic analysis of pathogenic and population missense variants in STXBP1. Mol Genet Genomic Med. 2017;5(5):495–507.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Schubert J, Siekierska A, Langlois M, May P, Huneau C, Becker F, et al. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes. Nat Genet. 2014;46(12):1327–32.

    Article  PubMed  CAS  Google Scholar 

  45. von Spiczak S, Helbig KL, Shinde DN, Huether R, Pendziwiat M, Lourenco C, et al. DNM1 encephalopathy: a new disease of vesicle fission. Neurology. 2017;89(4):385–94.

    Article  CAS  Google Scholar 

  46. Myers CT, Stong N, Mountier EI, Helbig KL, Freytag S, Sullivan JE, et al. De novo mutations in PPP3CA cause severe neurodevelopmental disease with seizures. Am J Hum Genet. 2017;101(4):516–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Duszyc K, Terczynska I, Hoffman-Zacharska D. Epilepsy and mental retardation restricted to females: X-linked epileptic infantile encephalopathy of unusual inheritance. J Appl Genet. 2015;56(1):49–56.

    Article  PubMed  Google Scholar 

  48. Depienne C, LeGuern E. PCDH19-related infantile epileptic encephalopathy: an unusual X-linked inheritance disorder. Hum Mutat. 2012;33(4):627–34.

    Article  PubMed  CAS  Google Scholar 

  49. •• Pederick DT, Richards KL, Piltz SG, Kumar R, Mincheva-Tasheva S, Mandelstam SA, et al. Abnormal cell sorting underlies the unique X-linked inheritance of PCDH19 epilepsy. Neuron. 2018;97(1):59–66. e5. This paper reports evidence to confirm the underlying mechanism for the unique female-limited X-linked inheritance pattern of PCDH19-related epilepsy.

    Article  PubMed  CAS  Google Scholar 

  50. de Lange IM, Rump P, Neuteboom RF, Augustijn PB, Hodges K, Kistemaker AI, et al. Male patients affected by mosaic PCDH19 mutations: five new cases. Neurogenetics. 2017;18(3):147–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. • Berg AT, Coryell J, Saneto RP, Grinspan ZM, Alexander JJ, Kekis M, et al. Early-life epilepsies and the emerging role of genetic testing. JAMA Pediatr. 2017;171(9):863–71. This study presents epidemiological evidence from a prospectively recruited cohort, demonstrating the utility of sequence-based genetic testing in early-life epilepsies.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Bartnik M, Szczepanik E, Derwinska K, Wisniowiecka-Kowalnik B, Gambin T, Sykulski M, et al. Application of array comparative genomic hybridization in 102 patients with epilepsy and additional neurodevelopmental disorders. Am J Med Genet B Neuropsychiatr Genet. 2012;159B(7):760–71.

    Article  PubMed  CAS  Google Scholar 

  53. Olson H, Shen Y, Avallone J, Sheidley BR, Pinsky R, Bergin AM, et al. Copy number variation plays an important role in clinical epilepsy. Ann Neurol. 2014;75(6):943–58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Michaud JL, Lachance M, Hamdan FF, Carmant L, Lortie A, Diadori P, et al. The genetic landscape of infantile spasms. Hum Mol Genet. 2014;23(18):4846–58.

    Article  PubMed  CAS  Google Scholar 

  55. Hrabik SA, Standridge SM, Greiner HM, Neilson DE, Pilipenko VV, Zimmerman SL, et al. The clinical utility of a single-nucleotide polymorphism microarray in patients with epilepsy at a tertiary medical center. J Child Neurol. 2015;30(13):1770–7.

    Article  PubMed  Google Scholar 

  56. Helbig I, Swinkels ME, Aten E, Caliebe A, van 't Slot R, Boor R, et al. Structural genomic variation in childhood epilepsies with complex phenotypes. Eur J Hum Genet. 2014;22(7):896–901.

    Article  PubMed  CAS  Google Scholar 

  57. Segal E, Pedro H, Valdez-Gonzalez K, Parisotto S, Gliksman F, Thompson S, et al. Diagnostic yield of epilepsy panels in children with medication-refractory epilepsy. Pediatr Neurol. 2016;64:66–71.

    Article  PubMed  Google Scholar 

  58. Mercimek-Mahmutoglu S, Patel J, Cordeiro D, Hewson S, Callen D, Donner EJ, et al. Diagnostic yield of genetic testing in epileptic encephalopathy in childhood. Epilepsia. 2015;56(5):707–16.

    Article  PubMed  CAS  Google Scholar 

  59. Della Mina E, Ciccone R, Brustia F, Bayindir B, Limongelli I, Vetro A, et al. Improving molecular diagnosis in epilepsy by a dedicated high-throughput sequencing platform. Eur J Hum Genet. 2015;23(3):354–62.

    Article  PubMed  CAS  Google Scholar 

  60. Wang J, Gotway G, Pascual JM, Park JY. Diagnostic yield of clinical next-generation sequencing panels for epilepsy. JAMA Neurol. 2014;71(5):650–1.

    Article  PubMed  Google Scholar 

  61. Lemke JR, Riesch E, Scheurenbrand T, Schubach M, Wilhelm C, Steiner I, et al. Targeted next generation sequencing as a diagnostic tool in epileptic disorders. Epilepsia. 2012;53(8):1387–98.

    Article  PubMed  CAS  Google Scholar 

  62. Veeramah KR, Johnstone L, Karafet TM, Wolf D, Sprissler R, Salogiannis J, et al. Exome sequencing reveals new causal mutations in children with epileptic encephalopathies. Epilepsia. 2013;54(7):1270–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Dyment DA, Tetreault M, Beaulieu CL, Hartley T, Ferreira P, Chardon JW, et al. Whole-exome sequencing broadens the phenotypic spectrum of rare pediatric epilepsy: a retrospective study. Clin Genet. 2015;88(1):34–40.

    Article  PubMed  CAS  Google Scholar 

  64. 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(5):664–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Golyala A, Kwan P. Drug development for refractory epilepsy: the past 25 years and beyond. Seizure. 2017;44:147–56.

    Article  PubMed  Google Scholar 

  66. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342(5):314–9.

    Article  PubMed  CAS  Google Scholar 

  67. • EpiPM Consortium. A roadmap for precision medicine in the epilepsies. Lancet Neurol. 2015;14(12):1219–28. This paper highlights the shift and current state of research in the genetic epilepsies.

    Article  PubMed Central  Google Scholar 

  68. Delanty N, Cavallleri G. Genomics-guided precise anti-epileptic drug development. Neurochem Res. 2017;42(7):2084–8.

    Article  PubMed  CAS  Google Scholar 

  69. •• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24. This paper outlines the methodology currently used by diagnostic laboratories for variant classification.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Vezyroglou K, Cross JH. Targeted treatment in childhood epilepsy syndromes. Curr Treat Options Neurol. 2016;18(6):29.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Mills PB, Struys E, Jakobs C, Plecko B, Baxter P, Baumgartner M, et al. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med. 2006;12(3):307–9.

    Article  PubMed  CAS  Google Scholar 

  72. Darin N, Reid E, Prunetti L, Samuelsson L, Husain RA, Wilson M, et al. Mutations in PROSC disrupt cellular pyridoxal phosphate homeostasis and cause vitamin-B6-dependent epilepsy. Am J Hum Genet. 2016;99(6):1325–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Plecko B, Zweier M, Begemann A, Mathis D, Schmitt B, Striano P, et al. Confirmation of mutations in PROSC as a novel cause of vitamin B6-dependent epilepsy. J Med Genet. 2017;54(12):809–14.

    Article  PubMed  Google Scholar 

  74. Boerma RS, Braun KP, van den Broek MP, van Berkestijn FM, Swinkels ME, Hagebeuk EO, et al. Remarkable phenytoin sensitivity in 4 children with SCN8A-related epilepsy: a molecular neuropharmacological approach. Neurotherapeutics. 2016;13(1):192–7.

    Article  PubMed  CAS  Google Scholar 

  75. Moller RS, Johannesen KM. Precision medicine: SCN8A encephalopathy treated with sodium channel blockers. Neurotherapeutics. 2016;13(1):190–1.

    Article  PubMed  Google Scholar 

  76. Schwabe MJ, Dobyns WB, Burke B, Armstrong DL. Valproate-induced liver failure in one of two siblings with Alpers disease. Pediatr Neurol. 1997;16(4):337–43.

    Article  PubMed  CAS  Google Scholar 

  77. • Baraban SC, Dinday MT, Hortopan GA. Drug screening in Scn1a zebrafish mutant identifies clemizole as a potential Dravet syndrome treatment. Nat Commun. 2013;4:2410. This paper displays the use of high-throughput drug screening as a way to identify targeted treatments in an animal model of genetic epilepsy.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Dinday MT, Baraban SC. Large-scale phenotype-based antiepileptic drug screening in a zebrafish model of Dravet syndrome. eNeuro. 2015;2(4). https://doi.org/10.1523/ENEURO.0068-15.2015.

  79. Ihara Y, Tomonoh Y, Deshimaru M, Zhang B, Uchida T, Ishii A, et al. Retigabine, a Kv7.2/Kv7.3-channel opener, attenuates drug-induced seizures in knock-in mice harboring Kcnq2 mutations. PLoS One. 2016;11(2):e0150095.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Pierson TM, Yuan H, Marsh ED, Fuentes-Fajardo K, Adams DR, Markello T, et al. Mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol. 2014;1(3):190–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Mikati MA, Jiang YH, Carboni M, Shashi V, Petrovski S, Spillmann R, et al. Quinidine in the treatment of KCNT1-positive epilepsies. Ann Neurol. 2015;78(6):995–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Bearden D, Strong A, Ehnot J, DiGiovine M, Dlugos D, Goldberg EM. Targeted treatment of migrating partial seizures of infancy with quinidine. Ann Neurol. 2014;76(3):457–61.

    Article  PubMed  CAS  Google Scholar 

  83. Abdelnour E, Gallentine W, McDonald M, Sachdev M, Jiang YH, Mikati MA. Does age affect response to quinidine in patients with KCNT1 mutations? Report of three new cases and review of the literature. Seizure. 2017;55:1–3.

    Article  PubMed  Google Scholar 

  84. • Sztainberg Y, Chen HM, Swann JW, Hao S, Tang B, Wu Z, et al. Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides. Nature. 2015;528(7580):123–6. This paper describes a method of manipulating gene expression as a potential therapeutic target.

    PubMed  PubMed Central  CAS  Google Scholar 

  85. • Hsiao J, Yuan TY, Tsai MS, Lu CY, Lin YC, Lee ML, et al. Upregulation of haploinsufficient gene expression in the brain by targeting a long non-coding RNA improves seizure phenotype in a model of Dravet syndrome. EBioMedicine. 2016;9:257–77. This paper describes a method of manipulating gene expression as a potential therapeutic target.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Perucca P, Scheffer IE, Harvey AS, James PA, Lunke S, Thorne N, et al. Real-world utility of whole exome sequencing with targeted gene analysis for focal epilepsy. Epilepsy Res. 2017;131:1–8.

    Article  PubMed  CAS  Google Scholar 

  87. Wilmshurst JM, Gaillard WD, Vinayan KP, Tsuchida TN, Plouin P, Van Bogaert P, et al. Summary of recommendations for the management of infantile seizures: task force report for the ILAE Commission of Pediatrics. Epilepsia. 2015;56(8):1185–97.

    Article  PubMed  Google Scholar 

  88. Carmichael N, Tsipis J, Windmueller G, Mandel L, Estrella E. “Is it going to hurt?”: the impact of the diagnostic odyssey on children and their families. J Genet Couns. 2015;24(2):325–35.

    Article  PubMed  Google Scholar 

  89. Basel D, McCarrier J. Ending a diagnostic odyssey: family education, counseling, and response to eventual diagnosis. Pediatr Clin North Am. 2017;64(1):265–72.

    Article  PubMed  Google Scholar 

  90. Rosell AM, Pena LD, Schoch K, Spillmann R, Sullivan J, Hooper SR, et al. Not the end of the odyssey: parental perceptions of whole exome sequencing (WES) in pediatric undiagnosed disorders. J Genet Couns. 2016;25(5):1019–31.

    Article  PubMed  Google Scholar 

  91. Farwell Hagman KD, Shinde DN, Mroske C, Smith E, Radtke K, Shahmirzadi L, et al. Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnosed diseases. Genet Med. 2017;19(2):224–35.

    Article  PubMed  CAS  Google Scholar 

  92. Kalia SS, Adelman K, Bale SJ, Chung WK, Eng C, Evans JP, et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med. 2017;19(2):249–55.

    Article  PubMed  Google Scholar 

  93. Dorschner MO, Amendola LM, Turner EH, Robertson PD, Shirts BH, Gallego CJ, et al. Actionable, pathogenic incidental findings in 1,000 participants’ exomes. Am J Hum Genet. 2013;93(4):631–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Acuna-Hidalgo R, Veltman JA, Hoischen A. New insights into the generation and role of de novo mutations in health and disease. Genome Biol. 2016;17(1):241.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Halvorsen M, Petrovski S, Shellhaas R, Tang Y, Crandall L, Goldstein D, et al. Mosaic mutations in early-onset genetic diseases. Genet Med. 2016;18(7):746–9.

    Article  PubMed  CAS  Google Scholar 

  96. •• Stosser MB, Lindy AS, Butler E, Retterer K, Piccirillo-Stosser CM, Richard G, et al. High frequency of mosaic pathogenic variants in genes causing epilepsy-related neurodevelopmental disorders. Genet Med. 2018;20(4):403–410. https://doi.org/10.1038/gim.2017.114. This paper is among the first to report on high rates of mosaicism for epilepsy-related gene variants in patients with epilepsy.

  97. •• Xu X, Yang X, Wu Q, Liu A, Yang X, Ye AY, et al. Amplicon resequencing identified parental mosaicism for approximately 10% of “de novo” SCN1A mutations in children with Dravet syndrome. Hum Mutat. 2015;36(9):861–72. This paper was the first to report high rates of parental mosaicism for the SCN1A gene.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Dibbens LM, Kneen R, Bayly MA, Heron SE, Arsov T, Damiano JA, et al. Recurrence risk of epilepsy and mental retardation in females due to parental mosaicism of PCDH19 mutations. Neurology. 2011;76(17):1514–9.

    Article  PubMed  CAS  Google Scholar 

  99. Walters J, Wells-Kilpatrick K, Pandeleos T. My epilepsy story—PCDH19 alliance. Epilepsia. 2014;55(7):968–9.

    Article  PubMed  Google Scholar 

  100. Pribaz E, Pribaz M. The Jack Pribaz Foundation and KCNQ2.org. Epilepsia. 2015;56(5):682–4.

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors wish to thank Ann Poduri, MD, MPH, for her critical feedback on this manuscript.

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Author notes

  1. Beth Rosen Sheidley, Lacey A. Smith and Katherine L. Helbig contributed equally to this work.

Authors and Affiliations

  1. Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital, 3 Blackfan Circle, Mail Stop BCH3149/CLS 14008, Boston, MA, 02115, USA

    Beth Rosen Sheidley & Lacey A. Smith

  2. Division of Neurology, Roberts Center for Pediatric Research, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Katherine L. Helbig

Authors
  1. Beth Rosen Sheidley
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  2. Lacey A. Smith
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  3. Katherine L. Helbig
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Correspondence to Beth Rosen Sheidley.

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Katherine L. Helbig reports personal fees from Ambry Genetics, outside of the submitted work. The other authors declare that they have no conflicts of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Genetic Counseling and Clinical Testing

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Sheidley, B.R., Smith, L.A. & Helbig, K.L. Genetics of Epilepsy in the Era of Precision Medicine: Implications for Testing, Treatment, and Genetic Counseling. Curr Genet Med Rep 6, 73–82 (2018). https://doi.org/10.1007/s40142-018-0139-8

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  • DOI: https://doi.org/10.1007/s40142-018-0139-8

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