Recent technological advances in gene sequencing have led to a rapid increase in gene discovery in epilepsy. However, the ability to assess pathogenicity of variants, provide functional analysis, and develop targeted therapies has not kept pace with rapid advances in sequencing technology. Thus, although clinical genetic testing may lead to a specific molecular diagnosis for some patients, test results often lead to more questions than answers. As the field begins to focus on therapeutic applications of genetic diagnoses using precision medicine, developing processes that offer more than equivocal test results is essential. The success of precision medicine in epilepsy relies on establishing a correct genetic diagnosis, analyzing functional consequences of genetic variants, screening potential therapeutics in the preclinical laboratory setting, and initiating targeted therapy trials for patients. The authors describe the structure of a comprehensive, pediatric Epilepsy Genetics Program that can serve as a model for translational medicine in epilepsy.
MeffordHCYendleSCHsuC. Rare copy number variants are an important cause of epileptic encephalopathies. Ann Neurol. 2011;70:974–985.
2.
VeeramahKRJohnstoneLKarafetTM. Exome sequencing reveals new causal mutations in children with epileptic encephalopathies. Epilepsia. 2013;54:1270–1281.
3.
AllenASBerkovicSFCossetteP. De novo mutations in epileptic encephalopathies. Nature. 2013;501:217–221.
4.
De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet. 2014;95:360–370.
5.
OlsonHShenYAvalloneJ. Copy number variation plays an important role in clinical epilepsy. Ann Neurol. 2014;75:943–958.
6.
PoduriASheidleyBRShostakSOttmanR. Genetic testing in the epilepsies-developments and dilemmas. Nat Rev Neurol. 2014;10:293–299.
7.
A roadmap for precision medicine in the epilepsies. Lancet Neurol. 2015;14:1219–1228.
8.
HelbigKLFarwell HagmanKDShindeDN. Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet Med. 2016;18:898–905.
HelbigILowensteinDH. Genetics of the epilepsies: where are we and where are we going?Curr Opin Neurol. 2013;26:179–185.
11.
Abou-KhalilBAlldredgeBBautistaJ. The epilepsy phenome/genome project. Clin Trials. 2013;10:568–586.
12.
Epi4 K: gene discovery in 4,000 genomes. Epilepsia. 2012;53:1457–1467.
13.
RichardsSAzizNBaleS. 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;17:405–424.
14.
GreenRCBergJSGrodyWW. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013;15:565–574.
15.
KrabbenborgLVissersLESchievingJ. Understanding the psychosocial effects of WES test results on parents of children with rare diseases. J Genet Couns. 2016;25:1207–1214.
16.
LandrumMJLeeJMBensonM. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016;44: D862–D868.
17.
LekMKarczewskiKJMinikelEV. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–291.
18.
FirthHVRichardsSMBevanAP. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet. 2009;84:524–533.
19.
MillsPBStruysEJakobsC. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med. 2006;12:307–309.
20.
PiersonTMYuanHMarshED. mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol. 2014;1:190–198.
21.
GunthorpeMJLargeCHSankarR. The mechanism of action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy. Epilepsia. 2012;53:412–424.
22.
BeardenD. Targeted treatment of migrating partial seizures of infancy with quinidine. Ann Neurol. 2014;76:457–461.
23.
GuerinAAzizASMutchCLewisJGoCYMercimek-MahmutogluS. Pyridox(am)ine-5-phosphate oxidase deficiency treatable cause of neonatal epileptic encephalopathy with burst suppression: case report and review of the literature. J Child Neurol. 2015;30:1218–1225.
24.
TorisuHWatanabeKShimojimaK. Girl with a PRRT2 mutation and infantile focal epilepsy with bilateral spikes. Brain Dev. 2014;36:342–345.
25.
LampertiCInvernizziFSolazziR. Clinical and genetic features of paroxysmal kinesigenic dyskinesia in Italian patients. Eur J Paediatr Neurol. 2016;20:152–157.
26.
HowellKBMcMahonJMCarvillGL. SCN2A encephalopathy: A major cause of epilepsy of infancy with migrating focal seizures. Neurology. 2015;85:958–966.
27.
BoermaRSBraunKPvan den BroekMP. Remarkable phenytoin sensitivity in 4 children with SCN8A-related epilepsy: a molecular neuropharmacological approach. Neurotherapeutics. 2016;13:192–197.
28.
WangDPascualJMDe VivoD. Glucose transporter type 1 deficiency syndrome. In: PagonRAAdamMPArdingerHH, eds. GeneReviews(R). Seattle, WA: University of Washington, Seattle; 1993–2016. Updated January 22, 2015.
29.
OverwaterIEBindels-de HeusKRietmanAB. Epilepsy in children with tuberous sclerosis complex: chance of remission and response to antiepileptic drugs. Epilepsia. 2015;56:1239–1245.
30.
MollerRSHeronSELarsenLH. Mutations in KCNT1 cause a spectrum of focal epilepsies. Epilepsia. 2015;56: e114–e120.
31.
PescosolidoMFSteinDMSchmidtM. Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome. Ann Neurol. 2014;76:581–593.
32.
WeckhuysenSIvanovicVHendrickxR. Extending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients. Neurology. 2013;81:1697–1703.
33.
ZonLI. Zebrafish: a new model for human disease. Genome Res. 1999;9:99–100.
34.
HoweKClarkMDTorrojaCF. The zebrafish reference genome sequence and its relationship to the human genome. Nature. 2013;496:498–503.
35.
UllmannJFCalamanteFCollinSPReutensDCKurniawanND. Enhanced characterization of the zebrafish brain as revealed by super-resolution track-density imaging. Brain Struct Funct. 2015;220:457–468.
36.
UllmannJFCowinGKurniawanNDCollinSP. A three-dimensional digital atlas of the zebrafish brain. NeuroImage. 2010;51:76–82.
37.
StewartAMUllmannJFNortonWH. Molecular psychiatry of zebrafish. Mol Psychiatry. 2015;20:2–17.
38.
BarabanSCTaylorMRCastroPABaierH. Pentylenetetrazole induced changes in zebrafish behavior, neural activity and c-fos expression. Neuroscience. 2005;131:759–768.
39.
BerghmansSHuntJRoachAGoldsmithP. Zebrafish offer the potential for a primary screen to identify a wide variety of potential anticonvulsants. Epilepsy Res. 2007;75:18–28.
40.
AfrikanovaTSerruysASBuenafeOE. Validation of the zebrafish pentylenetetrazol seizure model: locomotor versus electrographic responses to antiepileptic drugs. PLOS ONE. 2013;8: e54166.
41.
BarabanSCDindayMTHortopanGA. Drug screening in Scn1a zebrafish mutant identifies clemizole as a potential Dravet syndrome treatment. Nat Commun. 2013;4:2410.
