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The quest for juvenile myoclonic epilepsy genes

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The quest for juvenile myoclonic epilepsy genes
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  Review The quest for Juvenile Myoclonic Epilepsy genes Antonio V. Delgado-Escueta  a,b,c, ⁎ , Bobby P.C. Koeleman  e , Julia N. Bailey  a,b,d ,Marco T. Medina  b,f  , Reyna M. Durón  a,b,f  a Epilepsy Genetics/Genomics Laboratories, Neurology and Research Services, VA GLAHS-West Los Angeles, USA b GENESS International Consortium, USA c Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA d Department of Epidemiology, Fielding School of Public Health at UCLA, Los Angeles, CA, USA e Utrecht   —  Universitair Medisch Centrum Utrecht, Department of Medical Genetics, Division of Biomedical Genetics, The Netherlands f  Neurology Training Program, National Autonomous University of Honduras, Tegucigalpa, Honduras a b s t r a c ta r t i c l e i n f o  Article history: Accepted 29 June 2012 Keywords: LinkageGenome-wide associations Juvenile myoclonic epilepsy genes Introduced into a speci fi c population, a juvenile myoclonic epilepsy (JME) mutation generates  linkagedisequilibrium  (LD). Linkage disequilibrium is strongest when the JME mutation is of recent srcin, still “ hitchhiking ”  alleles surrounding it, as a haplotype into the next thousands of generations. Recombinationsdecay LD over tens of thousands of generations causing JME alleles to produce smaller genetic displacements,requiring other genes or environment to produce an epilepsy phenotype. Family-based linkage analysiscaptures rare epilepsy alleles and their  “ hitchhiking ”  haplotypes, transmitted as Mendelian traits, supportingthe common disease/multiple rare allele model. Genome-wide association studies identify JME alleles whoselinkage disequilibrium has decayed through thousands of generations and are sorting out the commondisease/common allele versus rare allele models. Five Mendelian JME genes have been identi fi ed, namely, CACNB4 ,  CASR ,  GABRa1 ,  GABRD , and  Myoclonin1/EFHC1.  Three SNP alleles in BRD2, Cx-36, and ME2 andmicrodeletions in 15q13.3, 15q11.2, and 16p13.11 also contribute risk to JME.  This article is part of a supplemental special issue entitled  Juvenile Myoclonic Epilepsy: What is it Really?  © 2012 Published by Elsevier Inc. 1. Introduction The epilepsies affect about 3 million people in the USA and65 million people in the world [1]. Amongst the heritable epilepsies, juvenile myoclonic epilepsy (JME) is the most common. Juvenile myo-clonic epilepsy is the most common idiopathic or genetic generalizedepilepsy and the most common cause of hereditary grand mal seizuresin people with epilepsy in the population at large [2,3]. Juvenile myo-clonic epilepsy has both Mendelian inheritance and complex geneticinheritance and accounts for 3% (population-based prevalence) to 12%(hospital/clinic-basedprevalence)ofallepilepsies[4,5].Forty-nineper-cent of our JME families have clinical and EEG traits that are  ‘ vertically ’ inheritedoverseveralgenerationssuggestinganautosomaldominantlyinherited disease. In the other 51%, variants of JME genes, with smalltomodesteffects,contributetorisk/susceptibilityandtoitscomplexge-netics. Presently, Mendelian JME genes and non-Mendelian risk alleleshave not been de fi ned in over 90% of affected patients. Consequently,nobody has found a cure for JME [6].How, then, are Mendelian genes that cause monogenic JME cap-tured within various populations of speci fi c countries worldwide?How do you identify the many single nucleotide polymorphisms(SNPs)/variants that increase risk for non-Mendelian complex JME?When and how did these epilepsy alleles arise? Why is it so impor-tant to identify these epilepsy alleles? 2. When did Mendelian or non-Mendelian complex JME genes fi rstmutate? How do such alleles increase in populations? Were epilepsy alleles already present in the human genome duringthe  fi rst successful migration of modern humans ( Homo SapiensSapiens )outoftheHornofAfrica60to100thousandyears(ka)ago?Mi-tochondrial and Y chromosome relics and haplogroups have recently re-vealedanancientancestrywithintheArabianPeninsulathatspreadfromAfrica and then through the Gulf oasis region toward the Near East andEurope55 – 24 kaago[7].DidepilepsymutationsariseduringthisspreadthroughtheGulfoasistotheNearEastandEurope?Ordidtheseepilepsyalleles arise during the dispersal of modern humans during late glacialand postglacial periods into Southwest Asia, Australasia, Southeast Asia,Central Europe, Siberia, and the Americas 50 to 20 ka ago [8 – 10]? Al-ternately, are epilepsy allelesBiblical, colonial, or modern, having mu-tated in the last 10 ka or last 600 years? Epilepsy & Behavior 28 (2013) S52 – S57 ⁎  Corresponding author at: Epilepsy Genetics/Genomics Laboratories, Comprehen-sive Epilepsy Program, David Geffen School of Medicine at UCLA and VA GLAHS-WestLos Angeles, Room 3049 (127B), Building 500, West Los Angeles VA Medical Center,11301 Wilshire Boulevard, Los Angeles, CA 90073, USA. Fax: +1 310 268 4937. E-mail address:  escueta@ucla.edu (A.V. Delgado-Escueta).1525-5050/$  –  see front matter © 2012 Published by Elsevier Inc.http://dx.doi.org/10.1016/j.yebeh.2012.06.033 Contents lists available at SciVerse ScienceDirect Epilepsy & Behavior  journal homepage: www.elsevier.com/locate/yebeh  Consider then the quest for these JME genes in our present time,when one or more of these epilepsy mutation(s) or JME alleles havemutated during dispersal from Africa(60 – 70 ka or 1800 – 2000 gener-ations ago) or during Biblical times (8 – 10 ka or 300 generations ago)orduringtheColonialera(0.5 kaor16 – 20generationsago)orduringmore recent modern periods of   Homo Sapiens Sapiens . Once intro-duced into a speci fi c population, an epilepsy mutation generateslinkage disequilibrium followed by subsequent drift and/or geneticselection. In this speci fi c population, the co-occurrence of speci fi cDNA markers and a JME mutation at a higher frequency than wouldbe predicted by random chance constitute linkage disequilibrium.In other words, DNA microsatellites or SNPs (single nucleotidepolymorphisms) and the JME mutation (allele) are physically close onthe DNA strand and occur together more often than can be accountedfor by chance.Once a JME mutation is introduced in a speci fi c population, howdoes it end up in greater numbers in such populations? Geneticselection, through inbreeding, famine, wars, and conquest such asthe colonization of the Americas and genocide like the Holocaust,could produce a population bottleneck that increases the frequencyof the newly created epilepsy allele within a speci fi c population[11]. Migration of a small proportion of individuals from the popula-tion to homestead a sparsely inhabited area would have a similarselecting effect.When this new epilepsy allele is transmitted to the next genera-tion, it brings the haplotype of other alleles linked to it in a segmentof a chromosome, along for the  “ ride ”  to the next generations, like a “ hitchhiking effect ”  [12] (Fig. 1). As mentioned above, the new epi- lepsy mutation/allele does not occur independently of surroundingalleles, microsatellites, and SNPs, and these chromosome loci are,therefore, in linkage disequilibrium. As time goes on and transmis-sions into more and more thousands of generations occur, linkagedisequilibriumdecaysthroughrecombinations.Thechromosomeseg-ment near the epilepsy allele is exchanged and crosses over withhomologous segments of other chromosomes which in turn carry dif-ferentallelesatnearbysitesoftheexchangingchromosome[11].Withmoreandmorerecombinations,thehitchhikedhaplotypeiseventual-ly lost, and the epilepsy allele has smaller and smaller genetic effects.Linkagedisequilibriumisstrongestandcoversthewidestregionof a chromosome when the epilepsy allele is of recent srcin (Biblical/300 generations ago or Colonial/16 – 20 generations ago), has not yetdecayed over many thousands of generations, and has large geneticeffects, e.g., Mendelian dominant or recessive effects. With more andmore thousands of generations and more migrations into outbredpopulations, more recombinations decay the linkage disequilibriumover the course of time, and epilepsy alleles over hundreds and thou-sands of generations decrease their genetic effects, produce smallergenetic displacements, and require other epilepsy alleles or environ-ment to produce the epilepsy phenotype.Here, in this Special Issue on Juvenile Myoclonic Epilepsy, we pres-ent an introduction/summary on Genetics of JME. B.P.C. Koeleman,then R. Buono and then Helbig, Hartmann and Mefford discuss thetwo methods and their results that are used to harness these epilepsyalleles. B.P.C. Koeleman used family based studies to capture themore rare photoparoxysmal epilepsy alleles and their "hitchhiking"haplotypes that are still transmitted as Mendelian traits (common JME disease/multiple rare epilepsy allele model). R. Buono usedGenome-wide association studies to identify the many epilepsy alleleswhose linkage disequilibrium has decayed through thousands of gen-erations and that are likely to be involved in the complex genetics of the more common outbred JME population (common JME disease/common epilepsy allele model versus rare epilepsy allele model). 3. Expanding the JME genome: massive parallel deepsequencing  —  whole genome or exome sequencing  Todate, fi veMendelianJMEgenesarelistedinOMIMorthe “ OnlineMendelianInheritanceinMan ” (http://omim.organdhttp://www.ncbi. nlm.nih.gov/omim/).Theseare CACNB4 ( calciumchannel beta4 subunit  )[13], CASR ( calciumchannelsensorreceptor  )[14], GABRa1 ( GABAreceptor alpha one subunit  ) [15],  GABRD  ( GABA receptor delta subunit  ) [16],and  Myoclonin1/EFHC1  ( myoclonin1/one EF  - hand containing gene ) [17](Table 1). Three SNP susceptibility alleles of putative JME genes inepistasis, namely, bromodomain-containing 2 (BRD2) [18], connexin36 (Cx-36) [19], and malic enzyme2 (ME2) [20] have been reported tobemajorsusceptibilityallelesthatcontributetothecomplexgenetics Fig. 1.  The haplotype  “ hitchhiking effect ” .S53  A.V. Delgado-Escueta et al. / Epilepsy & Behavior 28 (2013) S52 – S57   of JME [4,6]. Meanwhile, over 22 chromosome loci linked to JME haveyet to be unraveled for theirepilepsy genes (Table 1) [6]. The declining per unit cost and high throughput of deep sequencing of all humangenes for discovering allelic variants are now expanding the JME ge-nome. Massively parallel DNA sequencing technologies have renderedwhole exome sequencing (WES) or genome sequencing (WGS) of individual epilepsy patients increasingly practical [21 – 23]. However,around 24,000 individual genetic variations in a single individual'sexome(allexonicsequencesofallknownhumangenes)areonaverageobserved after deep sequencing. Therefore, extensive  fi ltering of detectedvariationhasbeendevisedspeci fi callyfortheepilepsygenome,rendering a more manageable number of putative disease variants for  Table 1  Juvenile myoclonic epilepsy genes and chromosome loci.ChromosomelocusHGNC gene symbol a or phenotypeGene/encoded protein Country/ethnic group/ancestral origin Mode of inheritance1p36.22 Absence and JME  Suggestive linkage  Europe (Germany, Netherlands, UK, France,Italy, and Greece)AD/oligogenic: meta analysisof 235 absence families and118 JME families1p36.33  EJM7 GABRD b Australian families incl GEFS+ AD2q23.3  EJM6 CACNB4 b One family (father and son with absencesand tonic – clonic) from Germany; onewoman with JME and a daughter with3-Hz spike wavesAD2q34 JME Unknown Europe (Germany, Netherlands, UK, France,Italy, and Greece)AD/oligogenic: meta analysisof 118 JME families2q23.3 and 2q24.1 JME Unknown Tunisia  —  one large consanguineous family AR 2q33 – 36  EJM9  Unknown India  —  one large 4 generation family AD3p14.2 JME/absence  Suggestive linkage  Europe(Germany, Netherlands, UK, France,Italy, and Greece)AD/oligogenic: meta analysisof 235 absence families and118 JME families3q21.1 JME  CASR   ( calcium sensor receptor gene ) b One large Indian family; 5 of 96 unrelated JME patients from Bangalore, IndiaAD5q12 – 14  EJM4  Unknown India AD5q35.3 JME with PPR (photosensitivity)Unknown Netherlands AD5q34  EJM5 GABRA 1 b French Canadian (Quebec, Canada)  —  onefamily; one absence patient from Germany;one absence patient from FranceAD5q34 (Absence and JME) Unknown Europe  —  Germany, Netherlands, UK, France,Italy, and GreeceAD/oligogenic: meta analysisof 235 absence families and118 JME families6p12  EJM1 Myoclonin1/EFHC1 b Hispanics [LA, California] ADHispanics [Belize]Hispanics [Mexico c ]Hispanics [Honduras and Mexico] JapanItaly and BrazilTennesseeAustria6p12 JME Unknown Netherlands AD6p21.3  EJM3 BRD2 c(bromodomain-containing gene) European descent [Los Angeles, California] AD/oligogenicEuropean descent [NY  c ];Germany6p20 JME  –  Germany AD6p21.2 JME  –  Germany AR 6q24 JME  –  Saudi Arabia AR 7q32 Photoparoxysmal response 3(PPR3), with or withoutmyoclonic epilepsyUnknown Netherlands16 multiplex familiesAD8q21.13 JME with PPR (photosensitivity) JRK, glutamate receptorGRIN2A are suspectedNetherlands AD10q25 – q26 JME with PPR   –  India (New Delhi), 5 families AD13q13 JME with PPR (photosensitivity) –  Netherlands AD13q31.3 CAE  –  Europe and Australia (Germany, Netherlands,UK, France, Italy and Greece)AR/meta analysis of 235absence families13q31 JME with PPR (photosensitivity)Netherlands, United Kingdom, Denmark,France, Greece, Portugal, SwedenAD15q14  Cx36 c (connexin36) or agap junction protein2 or GJP2European descent (New York) AR 15q14  EJM2  CHRNA7 is candidate gene UK, Sweden families AR 18q21 JME  ME2 c (malic enzyme2) European descent (New York) Association studies with JME19q13 Generalized epilepsy withfebrile seizures plus,including JME(GEFS+1) SCN1B  Europe and Australia (Germany,Netherlands, UK, France, Italy, and Greece)Meta analysis of 235 absenceand 118 JME familiesAR Xp11.4 – 11.3 JME  EFHC2  Germany, 81 patients Association study with JME a Human Genome Nomenclature Committee gene symbol in bold letters. b Mutation segregate with epilepsy affected members across 2 to 4 generation families or in singletons. c SNP-associated variants of BRD2, Cx36 and ME2; AD, autosomal dominant; AR, autosomal recessive; JME, juvenile myoclonic epilepsy; and pCAE, pyknoleptic childhoodabsence epilepsy.S54  A.V. Delgado-Escueta et al. / Epilepsy & Behavior 28 (2013) S52 – S57   follow-up. Typically, putative JME disease genes are identi fi ed throughevidence from familial segregation or association with disease. Withidenti fi cation of JME genes by deep sequencing, proof for causality byreplication of epilepsy phenotypes in knockout or knockin micemodelsoftheputativeepilepsygeneandpublichealthevidenceoftheirclinicalimportanceshoulddecidewhichepilepsygeneshavepriorityforstudiesofcuresandrepairs[6].Twogeneralapproacheshavebeenusedtomax-imize thepowerof deepsequencing andharness itforef  fi cientidenti fi -cation of JME genes [21 – 27]:(1) Family-based approach where linkage data, homozygosity map-ping and LOD score peaks in multiplex, multigeneration (Mg)familiesfocusthesearchfortheJME-causingSNPvariantstospe-ci fi c chromosome loci while family relations (sequencing affect-ed siblings and affected  fi rst degree cousins and affected distantrelatives) reduce the number of nonsynonymous SNP variantstobe fi ltered,excludingirrelevantpartsoftheexomeorgenomeprior to application of computational  fi lters. Chromosome re-gions that are identical by descent (IBD) can be inferred basedon the exome sequences of affected individuals using methodssuchasHiddenMarkovModel-basedalgorithms[21].Inconsan-guineous families, epilepsy-affected individuals share two iden-tical by descent (IBD) haplotypes inherited from a commonancestor. The putative JME gene must be located within the IBDhaplotype block.(2) Individual-based approach where affected individuals fromindependent kindreds with the same JME syndrome have WGor WE sequenced. In both approaches, SNP variants are  fi lteredagainst public SNP databases, and SNP variants commonlyshared by affected persons further identi fi ed for their potentialdisease mechanisms by neurobiological functions, evolutionaryconservation, and mutation impact (candidate genes) [27]. Anindividual exome usually has 20,000 to 30,000 variants. About10,000 of these variants lead to missense mutations, changesin conserved splice sites, or are small deletions or insertions.Almost 90% of these variants are in the dbSNP public SNP data-base, then the 5000 Genome Project and at private  “ in house ” exon data bases. Assuming that common variants are unlikelyto cause rare Mendelian diseases, such common variants are  fi l-tered out. Variants that are computationally predicted to be be-nignandnotpathogenicarealso fi lteredout[27].Theremainingvariants then, must be rare, expressed in the brain, and poten-tially epilepsy-causing. A candidate epilepsy gene should showat least one variant per affected individual in autosomal domi-nant JME. In autosomal recessive JME, each candidate epilepsygeneshould showhomozygous mutationsorcompoundhetero-zygous mutations [21 – 23].The individual-based approach works if the JME phenotype iscaused by one or two genotypes (minor amount of genetic heteroge-neity), and a search for the discovered JME gene can then be found inindividuals with the same JME phenotype. Until a second unrelatedindividual with JME or a second family with JME is found with a mu-tation in the same putative epilepsy gene, one can never be entirelycertain that a candidate epilepsy gene is in fact the sought after JMEgene.It is generally argued that with deep sequencing and the “ individual-based approach, ”  described above, large families are nolonger needed to de fi ne epilepsy genes. However, the individual-based approach is only now being tested in heritable epilepsieswhere phenotypic variability, misdiagnosis, genetic heterogeneity, andincomplete penetrance are most common. The ef  fi ciency of these twostudydesigns,thetimeef  fi ciencyoftheiranalysismethods,andsuccessratesinisolatingJME-causinggenesneedtobecomparedinthestudiesof genetic epilepsies. Both the  “ family-based approach ”  and the “ individual-based approach ”  should be validated and  fi ne-tuned ingenetic studies of JME.  3.1. De novo mutations Studies of copy number variations (CNVs) have demonstrated thecontributions of de novo mutations in the epilepsies (see Section 3).Copy number variations contribute to genetic generalized epilepsieswith complex inheritance, including JME. Recent experience withDravet syndrome, epilepsy combined with mental retardation withor without congenital anomalies/dysmorphisms, or epilepsy com-bined with autism show that de novo mutations have been underap-preciated in the epilepsies. The per generation mutation rate for denovo mutations is between 7.6×10 to 9th and 2.2×10 to the 8th orabout one in a hundred million positions in the haploid genome.Thiscorresponds to0.86 denovomutationspernewborn.Sequencingtrios (parents and affected proband) could identify pathogenic denovo mutations in the exome sequence of JME patients [22,23].  3.2. Whole exome sequencing (WES) versus whole genome sequencing (WGS) Because the majority of disease-causing mutations, characterizedto date, are located in exons, it is reasonable (it is also less costly) toconcentrate sequencing efforts on the approximate 1% of the humangenome that codes for protein sequences or WES. However, thecost of WGS continues to fall with each year, and data on the morecommon non-coding sequences and variants in distant enhancersand other regulatory elements are becoming available and associatedwith hereditary diseases.Various laboratories are claiming success rates of at least 50% inidentifying novel non-epilepsy disease genes using WGS or WES [23]. 4. Provingaputativemutationispathogenicandaputativeepilepsy gene is suf  fi cient by itself to cause epilepsy  The  fi rst step in proving that a Mendelian gene may be epilepsy-causingis toshowits mutationssegregateinaffected membersacross2 or more generations. This step was taken in the 5  fi ve Mendelian JME genes listed in OMIM or the  “ Online Mendelian Inheritance inMan ”  database (http://omim.org) and cited above (Table 1). Usually, the potential pathogenicity of a mutation is surmisedfrom (a) the domain sites of mutations and their potential deleteriouseffects on functions of the encoded protein as predicted by  “ in Silicoanalysis ”  and (b) location of mutations in evolutionarily conserveddomains. However, these prediction programs are not infallible, andmost investigators will show that a mutation may be epilepsy-causingby actually evaluating the functional consequences of the mutation.The second step, therefore, in proving that a Mendelian gene maybe epilepsy-causing, is to actually assess the purported function of the putative epilepsy gene and show that the mutation deleteriouslyaffects function of its encoded protein, a deleterious effect in a diseasebiochemical pathway that is potentially epileptogenic.This was done in 4 of the 5 Mendelian JME genes listed in OMIM,namely,  CACNB4 ,  GABRD ,  GABRA1 , and  Myoclonin1/EFHC1 . This hasyet to be done for  CASR . The altered biophysical properties of  CACNB4 ,  GABRD , and  GABRA1  that contained nucleotide mutationsand transfected in cell lines support a possible causal role in the JME phenotype observed in the patient/proband [13,28,29]. Inthe case of   Myoclonin1/EFHC1 , functional studies of individual mis-sense mutations supported a role in apoptosis and R-type VDCC.Overexpressionof   EFHC1 in mouse hippocampal primaryculture neu-rons induced apoptosis that was signi fi cantly decreased by each of  fi ve  EFHC1  missense mutations tested in hippocampal cells in culture.These missense mutations were double heterozygous 229C>A and662>A; 685T>C; 628 G>A; 757G>T; and 545G>A (4). In patchclamp analysis in HEK cell cultures,  EFHC1  speci fi cally increasedR-type Ca2+ currents that could increase apoptosis. The increased S55  A.V. Delgado-Escueta et al. / Epilepsy & Behavior 28 (2013) S52 – S57   R-type Ca2+ currents were partly reversed by each of   fi ve missensemutations [17].To investigate if a putative JME gene is suf  fi cient by itself toproduce an epilepsy phenotype, the third and  fi nal step is to targeta gene in embryonic stem cells and create strains of mice lackingthe putative epilepsy gene. This was done for  GABRD ,  GABRA1 , Myoclonin1/EFHC1,  and one of the susceptibility genes,  BRD2 . Sponta-neous seizures were not present in  GABRD − / − mice [30] indicatingthat  GABRD  was not suf  fi cient by itself to cause seizures and possiblyacts with other genes or environment to produce a JME phenotype. GABRD − / −  mice did have reduced pro-absence seizure effects(e.g.,ganaxalonefailedtoprolongPTZ-inducedabsence-likefreezing)suggesting it had a susceptibility role in absence seizures [30].In contrast, ethosuximide-sensitive spike-wave discharges andabsence-like seizures appeared in heterozygous GABRA1+/ −  miceand exhibited a female sex dependent effect on the spike-wavefrequency in C57BL/6J strain [31]. In the  fi rst generation of breedinghomozygous null mutants efhc1 − / −  mice and heterozygousefhc1+/ −  mice, spontaneous myoclonias with single or 2 diffuserapid spikes, low threshold to PTZ seizures, and large lateral ventri-cles were observed [32]. After seven generations of breeding, sponta-neous massive myoclonias and grand mal clonic-tonic-clonic seizureswith lower threshold to PTZ seizures as shown by death duringconvulsive status, are present in efhc1 − / − mice and efhc1+/ − mice(unpublished observations).Nature provided its own experiment when an inherited defect(a four-nucleotide insertion into a splice donor site resulting inexon skipping, frameshift, and truncation with loss of alpha1 bindingsites) in Cchb4 in mouse chromosome 2, the mice homologue of human  CACNB4 , produced absence-like seizures and ataxia. Thesemice are called  Tottering mice  [33].In the case of the bromodomain-containing gene BRD2, a null mu-tation of the homologous BRD2 locus results in embryonic lethality,while heterozygous BRD2+/ − males have decreased clonic andfemales have decreased tonic-clonic seizure threshold to  fl urothyl.Spontaneous seizures also appear in BRD2+/ − female mice [34].In summary, mutations in Cchb4, the mouse homologue of human CACNB4  or mutations in  GABRA1  are suf  fi cient by themselves to pro-duce the absence phenotype while mutations in  Myoclonin1/efhc1  or BRD2  are suf  fi cient by themselves to produce a convulsive phenotype(myoclonic or clonic or tonic-clonic seizures). 5. Why is it important to identify JME alleles? Identifying epilepsy alleles that cause JME is important for thefollowing reasons:(1) Targeteddesignerantiepilepticdrugs:Aseachangeisoccurringinthedevelopmentofantiepilepticdrugs(AEDs)withthereal-ization that drugs developed against genetic epilepsies workagainst both genetic generalized epilepsies and symptomaticlesional epilepsies but not the other way around. In the past,development of AEDs relied on the use of animal models of seizures and animal models of animal epilepsies. Only recentlyhas an AED been developed against a mouse model of humangenetic epilepsy, namely, the seizure threshold-1 (Szt1), akcnq2 knockout mice. Retigabine, an M-channel enhancer,decreasedseizuresensitivityofmicecarryingtheszt1mutationwhich deletes the C-terminus of mouse  kcnq2  [35]. Themyoclonin/efhc1 KO model and the tottering mice can beused as a test model for developing AEDs against JME.(2) Advanced brain imaging in  myoclonin/efhc1  KO mice,  BRD2  KOmice, and tottering mice can decide if striato-thalamic-frontalcortical MRI changes in human JME are part of the JME geno-type, the JME network for seizures or the consequences of seizures. Woermann[seeelsewhereinthis Supplement] showedbrainimagingabnormalitiesinthedorsolateralprefrontalcortex,premotor cortex, basal frontal cortex, thalamus, and putamen inhuman JME [36]. What remains unclear is  —  which anatomicalnetworks are part of the genotype, which anatomical networksare effects of the myoclonias and tonic-clonic convulsions, andwhich anatomical networks subserve seizures and epilepsy?Since rarely, if ever, do we have access to JME human brains toanswer these questions, MRI studies and neuropathologicalstudies of   efhc1 −  /  −  mice brains, brd2 − / −  mice brains, andtottering (cacnb4 − / − ) mice brains could help.(3) Identifyingmutationsinepilepsygenescanleadtogenotypingof epilepsy genes, improved and early diagnosis, and early curativetreatment [37].Following this introduction/summary of JME genetics, B.P.C.Koeleman discusses epilepsy alleles that are still transmitted with"hitchhiking haplotypes" in families with EEG photoparoxysmal re-sponse and/or clinical sensitivity to light. Epilepsy alleles that have sur-vived transmission through thousands of generations but may havereduced the size of or lost their  “ hitchhiking haplotypes ”  are capturedby GWAS in R.J. Buono's studies. The unexpected contribution of copynumber variations to JME risk is highlighted by Helbig, Hartmann,and Mefford. Of the  fi ve JME Mendelian genes,  Myoclonin1/EFHC1  hasreceived special attention because it appears to have been geneticallyselected in speci fi c populations, responsible for 3 to 9% of JME invarious populations worldwide.  Myoclonin1/EFHC1  has also assumedmore importance now that it is clear that a single copy of its mutation,transmitted as an autosomal dominant gene, produces adolescentmyoclonias and grandmal convulsions (JME), while two copies of its mutation, transmitted as an autosomal recessive gene, produce asevere intractable epilepsy of infancy with death at 3 to 96 months.Thus, the functions of myoclonin1/EFHC1 in brain development arediscussed by de Nijs et al. and Yamakawa and Suzuki. Con fl ict of interest The authors declare that there are no con fl icts of interest. References [1] HauserWA, Hesdorffer DC. Epilepsy-frequency,causesand consequences. LandoverMD: Demos; 1990.[2] Janz D. Die Epilepsien. 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