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Epilepsy-associated genes

  • Author Footnotes
    1 These authors contributed equally to this work.
    Jie Wang
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China

    Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Zhi-Jian Lin
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China

    Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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  • Liu Liu
    Affiliations
    Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China

    Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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  • Hai-Qing Xu
    Affiliations
    Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China

    Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China

    Department of Neurology, Affiliated Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
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  • Yi-Wu Shi
    Affiliations
    Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China

    Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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  • Yong-Hong Yi
    Affiliations
    Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China

    Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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  • Na He
    Correspondence
    Corresponding authors at: Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medica University, Chang-Gang-Dong Road 250, Guangzhou 510260, China. Fax: +86 20 34153378.
    Affiliations
    Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China

    Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
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  • Author Footnotes
    2 One of the authors of this paper is a member of the current editorial team of Seizure. The supervision of the independent peer review process was undertaken and the decision about the publication of this manuscript were made by other members of the editorial team.
    Wei-Ping Liao
    Correspondence
    Corresponding authors at: Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medica University, Chang-Gang-Dong Road 250, Guangzhou 510260, China. Fax: +86 20 34153378.
    Footnotes
    2 One of the authors of this paper is a member of the current editorial team of Seizure. The supervision of the independent peer review process was undertaken and the decision about the publication of this manuscript were made by other members of the editorial team.
    Affiliations
    Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China

    Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
    2 One of the authors of this paper is a member of the current editorial team of Seizure. The supervision of the independent peer review process was undertaken and the decision about the publication of this manuscript were made by other members of the editorial team.
Open ArchivePublished:December 06, 2016DOI:https://doi.org/10.1016/j.seizure.2016.11.030

      Highlights

      • We summarized 977 epilepsy-associated genes, which were divided into 4 categories according to the manifestation of epilepsy in phenotypes.
      • 84 epilepsy genes, i.e., genes that only cause epilepsies or syndromes with epilepsy as the core symptom.
      • 73 neurodevelopment-associated genes, i.e., genes associated with gross brain developmental malformations and epilepsies.
      • 536 epilepsy-related genes, i.e., genes associated with gross physical, or other systemic abnormalities and accompanied by epilepsy or seizures.
      • 284 potential epilepsy-associated genes, i.e., genes that require further verification.

      Abstract

      Development in genetic technology has led to the identification of an increasing number of genes associated with epilepsy. These discoveries will both provide the basis for including genetic tests in clinical practice and improve diagnosis and treatment of epilepsy. By searching through several databases (OMIM, HGMD, and EpilepsyGene) and recent publications on PubMed, we found 977 genes that are associated with epilepsy. We classified these genes into 4 categories according to the manifestation of epilepsy in phenotypes. We found 84 genes that are considered as epilepsy genes: genes that cause epilepsies or syndromes with epilepsy as the core symptom. 73 genes were listed as neurodevelopment-associated genes: genes associated with both brain-development malformations and epilepsy. Several genes (536) were epilepsy-related: genes associated with both physical or other systemic abnormalities and epilepsy or seizures. We found 284 additional genes putatively associated with epilepsy; this requires further verification. These integrated data will provide new insights useful for both including genetic tests in the clinical practice and evaluating the results of genetic tests. We also summarized the epilepsy-associated genes according to their function, with the goal to better characterize the association between genes and epilepsies and to further understand the mechanisms underlying epilepsy.

      Keywords

      1. Introduction

      Advances in genomics techniques, especially the development of next-generation sequencing, have greatly increased our knowledge on the genetic changes occurring across the entire human genome, allowing for rapid and efficient discovery of genes involved in many diseases. Epilepsies may result from primary genetic abnormalities or secondary to well-defined structural or metabolic disorders, of which, some also have genetic causes. It is estimated that more than half of epilepsies have a genetic basis [
      • Pal D.K.
      • Pong A.W.
      • Chung W.K.
      Genetic evaluation and counseling for epilepsy.
      ]. The application of genomic technologies has a tremendous impact on the discovery of the genetic basis of epilepsy, and it is expected to play a pivotal role in the diagnosis and treatment of epilepsy. However, epilepsies associated with genetic abnormalities display large heterogeneity. Mutations in some genes may selectively cause epilepsies or syndromes with epilepsy as the core symptom (e.g., SCN1A mutations cause epilepsies with febrile seizures plus [
      • Meng H.
      • Xu H.Q.
      • Yu L.
      • Lin G.W.
      • He N.
      • Su T.
      • et al.
      The SCN1A mutation database: updating information and analysis of the relationships among genotype, functional alteration, and phenotype.
      ]), while other genes may be associated with gross brain developmental malformations and epilepsies (e.g., mutations in TSC1 and TSC2 genes cause tuberous sclerosis [
      • Nellist M.
      • van den Heuvel D.
      • Schluep D.
      • Exalto C.
      • Goedbloed M.
      • Maat-Kievit A.
      • et al.
      Missense mutations to the TSC1 gene cause tuberous sclerosis complex.
      ,
      • Jansen A.C.
      • Sancak O.
      • D’Agostino M.D.
      • Badhwar A.
      • Roberts P.
      • Gobbi G.
      • et al.
      Unusually mild tuberous sclerosis phenotype is associated with TSC2 R905Q mutation.
      ]). Seizures may also occur in other genetic disorders affecting the central nervous system, such as Fragile X Syndrome [
      • Gronskov K.
      • Brondum-Nielsen K.
      • Dedic A.
      • Hjalgrim H.
      A nonsense mutation in FMR1 causing fragile X syndrome.
      ] and myoclonus-dystonia [
      • Foncke E.M.
      • Klein C.
      • Koelman J.H.
      • Kramer P.L.
      • Schilling K.
      • Muller B.
      • et al.
      Hereditary myoclonus-dystonia associated with epilepsy.
      ]. Therefore, it is a challenge to decide which gene, or group of genes, should be characterized in a specific target patient population before designing an efficient and cost-effective genetic-testing strategy. In this review, we present a summary of the genes associated with epilepsy. We grouped the genes according to the manifestation of epilepsy in the phenotype, i.e., whether epilepsy is the exclusive outcome of the mutation or part of a group of unrelated symptoms. The aim of the present review is to offer an insight into the genes that should be included in the genetic testing of patients with a distinct phenotype. The association between genes and epilepsy will further our knowledge on the role played by specific mutations in epilepsy and the mechanisms underlying epileptogenesis.

      2. Methods

      To obtain a comprehensive list of genes associated with epilepsy, a thorough search of online databases was conducted. Briefly, we searched the Online Mendelian Inheritance in Man database (OMIM, http://www.ncbi.nlm.nih.gov/omim/) with the following query terms: “epilepsy/epilepsies/epileptic” or “seizure/seizures.” We then crosschecked the findings with the results from the searches performed on the Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/index.php) and the EpilepsyGene database (http://61.152.91.49/EpilepsyGene/). Additionally, recent publications relevant to epilepsy were searched on PubMed (http://www.ncbi.nlm.nih.gov/pubmed/).
      More than 2000 items were retrieved from the OMIM database. These items were further analyzed through thorough reading and double-checked manually by two experts in the field of epilepsy. The items related to epilepsy and well-characterized gene mutations were included. We used the following criteria to exclude articles from the analysis: (1) clinical genetic reports without definite molecular genetic confirmation, (2) linkage analysis without identification of specific genes, (3) genomic rearrangement without the causative gene defined, (4) clinical syndrome potentially related to epilepsy; however, the patients with epilepsy were not subjected to a genetic test. Finally, 693 genes were identified to be associated with epilepsy. The phenotypes of these genes exhibit a large variability in epilepsy and other clinical manifestations. According to the manifestation of epilepsy in phenotypes, these genes were divided into 3 categories: (1) epilepsy genes, i.e., genes that only cause epilepsies or syndromes with epilepsy as the core symptom; (2) neurodevelopment-associated epilepsy genes, i.e., genes associated with gross brain developmental malformations and epilepsies; and (3) epilepsy-related genes, i.e., genes associated with gross physical, or other systemic abnormalities and accompanied by epilepsy or seizures.
      After crosschecking the HGMD and EpilepsyGene databases, we found 247 additional genes, not present in the OMIM database, potentially associated with epilepsy. We did not include the 248 genes that were presented in the EpilepsyGene database but were not described to be associated with epilepsy in the original report [
      • Epi4K Consortium
      • Epilepsy Phenome/Genome Project
      • Allen A.S.
      • Berkovic S.F.
      • Cossette P.
      • Delanty N.
      • et al.
      De novo mutations in epileptic encephalopathies.
      ]. Furthermore, considering that some of the genes which have been recently reported to be involved in epilepsy may not be present in any of the three databases, we searched PubMed for recent publications (i.e., since 2014) relevant to epilepsy. This last search yielded 37 more genes potentially associated with epilepsy.

      3. Results

      3.1 Epilepsy genes

      Based on the results from the search in the OMIM database, 84 genes were classified as epilepsy genes. Mutations in these genes cause pure or relatively pure epilepsies, or syndromes with epilepsy as the core symptom. This category also includes genes that may be associated with multiple phenotypes other than epilepsy or seizures; however, an individual with mutations in these genes may present only epilepsy or seizures. For example, PRRT2 mutations are associated with several clinical syndromes such as paroxysmal dyskinesia, infantile convulsions with paroxysmal choreoathetosis, and benign familial infantile seizures [
      • Liu X.R.
      • Wu M.
      • He N.
      • Meng H.
      • Wen L.
      • Wang J.L.
      • et al.
      Novel PRRT2 mutations in paroxysmal dyskinesia patients with variant inheritance and phenotypes.
      ]. Although paroxysmal dyskinesia is the main symptom in the majority of patients, there are cases of only benign familial infantile seizures in individuals harboring this mutation. To facilitate the search for causative genes, we present a summary of these genes according to their phenotypes and sorted according to their onset age (Table 1).
      Table 1Epilepsy genes.
      Phenotype (in order of the onset age)InheritanceGene
      Neonatal
       Pyridoxamine 5'-phosphate oxidase deficiency (PNPOD)ARPNPO
       Pyridoxine-dependent epilepsy (EPD)ARALDH7A1
       Benign familial neonatal seizures (BFNS)ADKCNQ2, KCNQ3
      Infantile and childhood
       Familial infantile myoclonic epilepsy (FIME)ARTBC1D24
       Benign familial infantile seizures (BFIS)ADPRRT2, SCN2A, SCN8A
       Amish infantile epilepsy syndrome (AIES)ARST3GAL5
       Early infantile epileptic encephalopathy (EIEE)ADCACNA1A, GABRA1, GABRB3, KCNQ2, KCNT1, SCN2A, SCN8A
      ARAARS, ARV1, DOCK7, FRRS1L, GUF1, ITPA, NECAP1, PLCB1, SLC12A5, SLC13A5, SLC25A12, SLC25A22, ST3GAL3, SZT2, TBC1D24, WWOX
      XLDCDKL5
      XLRARHGEF9
      XLALG13, PCDH19
      UNDNM1, EEF1A2, FGF12, GABRB1, GNAO1, GRIN2B, GRIN2D, HCN1, KCNA2, KCNB1, SIK1, SLC1A2, SPTAN1, STXBP1, UBA5
       Dravet syndrome (DS)ADSCN1A, SCN9A
      Potential modifier gene.
       Familial febrile seizures (FFS)ADGABRG2, GPR98, SCN1A, SCN9A
      ARCPA6
       Generalized epilepsy with febrile seizures plus (GEFS + )ADGABRD, GABRG2, SCN1A, SCN1B, SCN9A, STX1B
       Generalized epilepsy and paroxysmal dyskinesia (GEPD)ADKCNMA1
       Myoclonic-atonic epilepsy (MAE)ADSLC6A1
       Childhood-onset epileptic encephalopathy (COEE)ADCHD2
       Focal epilepsy and speech disorder (FESD) with or without mental retardationADGRIN2A
       Childhood absence epilepsy (CAE)ADGABRG2
      UNCACNA1H, GABRA1, GABRB3
      Juvenile and later
       Juvenile absence epilepsy (JAE)ADCLCN2
      Description on phenotype was modified after retraction of the initial report.
      , EFHC1
       Juvenile myoclonic epilepsy (JME)ADCACNB4, CLCN2
      Description on phenotype was modified after retraction of the initial report.
      , EFHC1, GABRD
      UNGABRA1
       Idiopathic generalized epilepsy (IGE)ADCACNB4, CLCN2
      Description on phenotype was modified after retraction of the initial report.
      , GABRD, SLC12A5, SLC2A1
      UNCACNA1H, CASR
       Familial adult myoclonic epilepsy (FAME)ADADRA2B
      ARCNTN2
       Familial temporal lobe epilepsy (FTLE)ADCPA6, GAL, LGI1
      Not specific
       Progressive myoclonic epilepsy (PME)ADKCNC1
      ARCERS1, CSTB, EPM2A, GOSR2, KCTD7, LMNB2, NHLRC1, PRDM8, PRICKLE1, SCARB2
       Nocturnal frontal lobe epilepsy (NFLE)ADCHRNA2, CHRNA4, KCNT1
      UNCHRNB2
       Familial focal epilepsy with variable foci (FFEVF)ADDEPDC5
      Bold italics, with multiple epilepsy phenotypes.
      AD, autosomal dominant; AR, autosomal recessive; UN, unknown; XL, X-linked; XLD, X-linked dominant; XLR, X-linked recessive.
      AARS, alanyl-tRNA synthetase; ADRA2B, alpha-2B-adrenergic receptor; ALDH7A1, aldehyde dehydrogenase 7 family, member A1; ALG13, asparagine-linked glycosylation 13, S. cerevisiae, homolog of; ARHGEF9, RHO guanine nucleotide exchange factor 9; ARV1, ARV1, S. cerevisiae, homolog of; ​CACNA1A, calcium channel, voltage-dependent, P/Q type, alpha-1A subunit; CACNA1H, calcium channel, voltage-dependent, T type, alpha-1H subunit; CACNB4, calcium channel, voltage-dependent, beta-4 subunit; CASR, calcium-sensing receptor; CDKL5, cyclin-dependent kinase-like 5; CERS1, ceramide synthase 1; CHD2, chromodomain helicase DNA-binding protein 2; CHRNA2, cholinergic receptor, neuronal nicotinic, alpha polypeptide 2; CHRNA4, cholinergic receptor, neuronal nicotinic, alpha polypeptide 4; CHRNB2, cholinergic receptor, neuronal nicotinic, beta polypeptide 2; CLCN2, chloride channel 2; CNTN2, contactin 2; CPA6, carboxypeptidase A6; CSTB, cystatin B; DEPDC5, DEP domain-containing protein 5; DNM1, dynamin 1; DOCK7, dedicator of cytokinesis 7; EEF1A2, eukaryotic translation elongation factor 1, alpha-2; EFHC1, EF-hand domain (C-terminal)-containing protein 1; EPM2A, EPM2A gene, encodes laforin; FGF12, fibroblast growth factor 12; FRRS1L, ferric chelate reductase 1-like; GABRA1, gamma-aminobutyric acid receptor, alpha-1; GABRB1, gamma-aminobutyric acid receptor, beta-1; GABRB3, gamma-aminobutyric acid receptor, beta-3; GABRD, gamma-aminobutyric acid receptor, delta; GABRG2, gamma-aminobutyric acid receptor, gamma-2; GAL, galanin; GNAO1, guanine nucleotide-binding protein, alpha-activating activity polypeptide O; GOSR2, golgi snap receptor complex member 2; GPR98, G protein-coupled receptor 98; GRIN2A, glutamate receptor, ionotropic, N-methyl-D-aspartate, subunit 2A; GRIN2B, glutamate receptor, ionotropic, N-methyl-D-aspartate, subunit 2B; GRIN2D, glutamate receptor, ionotropic, N-methyl-D-aspartate, subunit 2D; GUF1, GUF1 GTPase, S. cerevisiae, homolog of; HCN1, hyperpolarization-activated cyclic nucleotide-gated potassium channel 1; ITPA, inosine triphosphatase; KCNA2, potassium channel, voltage-gated, shaker-related subfamily, member 2; KCNB1, potassium channel, voltage-gated, shab-related subfamily, member 1; KCNC1, potassium channel, voltage-gated, shaw-related subfamily, member 1; KCNMA1, potassium channel, calcium-activated, large conductance, subfamily M, alpha member 1; KCNQ2, potassium channel, voltage-gated, KQT-like subfamily, member 2; KCNQ3, potassium channel, voltage-gated, KQT-like subfamily, member 3; KCNT1, potassium channel, subfamily T, member 1; KCTD7, potassium channel tetramerization domain-containing protein 7; LGI1, leucine-rich gene, glioma-inactivated, 1; LMNB2, lamin B2; NECAP1, NECAP endocytosis-associated protein 1; NHLRC1, NHL repeat-containing 1 gene; PCDH19, protocadherin 19; PLCB1, phospholipase C, beta-1; PNPO, pyridoxamine 5-prime-phosphate oxidase; PRDM8, PR domain-containing protein 8; PRICKLE1, prickle, drosophila, homolog of, 1; PRRT2, proline-rich transmembrane protein 2; SCARB2, scavenger receptor class B, member 2; SCN1A, sodium channel, neuronal type I, alpha subunit; SCN1B, sodium channel, voltage-gated, type I, beta subunit; SCN2A, sodium channel, voltage-gated, type II, alpha subunit; SCN8A, sodium channel, voltage-gated, type VIII, alpha subunit; SCN9A, sodium channel, voltage-gated, type IX, alpha subunit; SIK1, salt-inducible kinase 1; SLC1A2, solute carrier family 1 (glial high affinity glutamate transporter), member 2; SLC12A5, solute carrier family 12 (potassium/chloride transporter), member 5; SLC13A5, solute carrier family 13 (sodium-dependent citrate transporter), member 5; SLC25A12, solute carrier family 25 (mitochondrial carrier, aralar), member 12; SLC25A22, solute carrier family 25 (mitochondrial carrier, glutamate), member 22; SLC2A1, solute carrier family 2 (facilitated glucose transporter), member 1; SLC6A1, solute carrier family 6 (neurotransmitter transporter, gaba), member 1; SPTAN1, spectrin, alpha, nonerythrocytic 1; ST3GAL3, ST3 beta-galactoside alpha-2,3-sialyltransferase 3; ST3GAL5, ST3 beta-galactoside alpha-2,3-sialyltransferase 5; STX1B, syntaxin 1B; STXBP1, syntaxin-binding protein 1; SZT2, seizure threshold 2, mouse, homolog of; TBC1D24, Tre2-Bub2-Cdc16/TBC1 domain family, member 24; UBA5, ubiquitin-like modifier activating enzyme 5; WWOX, WW domain-containing oxidoreductase.
      a Description on phenotype was modified after retraction of the initial report.
      b Potential modifier gene.
      The spectrum of epilepsy caused by gene mutations covers 23 epileptic phenotypes, ranging from the mild form of benign familial infantile seizures to the extremely severe form of early infantile epileptic encephalopathy (EIEE). More than one causative gene has been identified in 14 epileptic phenotypes. EIEE was shown to be associated with mutations in 42 genes. Progressive myoclonic epilepsy was associated with 11 pathogenic genes. Other common phenotypes with multiple genetic causes are mostly represented by idiopathic epilepsies including childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and idiopathic generalized epilepsy. In contrast, only a single causative gene has been identified in 9 epileptic phenotypes. However, except for few cases with definite one-to-one epilepsy to gene correlation such as myoclonic-atonic epilepsy and SLC6A1, more than one genetic cause is generally expected to be identified in most of the phenotypes. For instance, CHRNA4 was initially identified as the only pathogenic gene of nocturnal frontal lobe epilepsy [
      • Steinlein O.K.
      • Mulley J.C.
      • Propping P.
      • Wallace R.H.
      • Phillips H.A.
      • Sutherland G.R.
      • et al.
      A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy.
      ]; however, later studies demonstrated that CHRNB2, CHRNA2, and KCNT1 were also associated with this type of epilepsy [
      • De Fusco M.
      • Becchetti A.
      • Patrignani A.
      • Annesi G.
      • Gambardella A.
      • Quattrone A.
      • et al.
      The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy.
      ,
      • Aridon P.
      • Marini C.
      • Di Resta C.
      • Brilli E.
      • De Fusco M.
      • Politi F.
      • et al.
      Increased sensitivity of the neuronal nicotinic receptor alpha 2 subunit causes familial epilepsy with nocturnal wandering and ictal fear.
      ,
      • Heron S.E.
      • Smith K.R.
      • Bahlo M.
      • Nobili L.
      • Kahana E.
      • Licchetta L.
      • et al.
      Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy.
      ].
      The causative genes produce large variation in the inheritance pattern of the genetic epilepsies. The inheritance pattern has commonly been classified into dominant (autosomal or X-linked) or recessive (autosomal or X-linked) inheritance. However, recent studies have identified epilepsy genes with undefined inheritance, including genes with de novo mutations. De novo mutations may be associated with autosome dominant genetic disorders, such as the spectrum of epilepsies with febrile seizures plus caused by SCN1A mutations, typically in Dravet syndrome [
      • Meng H.
      • Xu H.Q.
      • Yu L.
      • Lin G.W.
      • He N.
      • Su T.
      • et al.
      The SCN1A mutation database: updating information and analysis of the relationships among genotype, functional alteration, and phenotype.
      ]. De novo mutations have been frequently identified in epileptic encephalopathies [
      • Suls A.
      • Jaehn J.A.
      • Kecskes A.
      • Weber Y.
      • Weckhuysen S.
      • Craiu D.C.
      • et al.
      De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome.
      ,
      • EuroEPINOMICS-RES Consortium
      • Epilepsy Phenome/Genome Project
      • Epi4K Consortium
      De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies.
      ,
      • Ohba C.
      • Kato M.
      • Takahashi N.
      • Osaka H.
      • Shiihara T.
      • Tohyama J.
      • et al.
      De novo KCNT1 mutations in early-onset epileptic encephalopathy.
      ,
      • Kodera H.
      • Ohba C.
      • Kato M.
      • Maeda T.
      • Araki K.
      • Tajima D.
      • et al.
      De novo GABRA1 mutations in Ohtahara and West syndromes.
      ]. However, as many of these children with neurodisability did not reproduce, it was unclear as to whether these are de novo dominant mutations. An exception is that EIEE caused by PCDH19 mutations included de novo mutations, but presented an inheritance of neither X-linked dominant nor recessive. EIEE displayed heterogeneity in both the genetic cause and the inheritance pattern. It is noteworthy that epileptic encephalopathies encompass several clinical subtypes such as the Lennox–Gastaut syndrome, the West syndrome, and the Landau–Kleffner syndrome. We failed to identify genetic information for each of the syndromes separately owing to the lack of detailed information available in OMIM or publications.
      To better understand the molecular characteristics of the products of epilepsy genes, we grouped the genes according to the protein function (Table 2). The most common epilepsy genes were ion-channel genes, which account for 28 of the 84 epilepsy genes, indicating that ion-channel genes may play an important role in epilepsy. Mutations in ion-channel genes produce a variety of epilepsies with phenotypes ranging from mild to severe. Mutations in enzyme/enzyme-modulator genes ranked as the second cause (25/84); these mainly caused the severe form of epilepsy, except mutations in CPA6 gene which cause relatively mild familial temporal-lobe epilepsy and familial febrile seizures [
      • Salzmann A.
      • Guipponi M.
      • Lyons P.J.
      • Fricker L.D.
      • Sapio M.
      • Lambercy C.
      • et al.
      Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy.
      ]. The remaining genes included in the analysis are involved in transport, receptor binding, cell adhesion, signal transduction/molecule, membrane trafficking, cytoskeleton, nucleic acid binding, and other unknown functions.
      Table 2Functional categories of the epilepsy genes.
      Encoded protein functionGene and phenotype (OMIM phenotype)
      Ion channel
       Sodium channelSCN1A (DS/GEFS+/FFS), SCN1B (GEFS + ), SCN2A (EIEE/BFIS), SCN8A (EIEE/BFIS), SCN9A (GEFS+/DS/FFS)
       Potassium channelKCNA2 (EIEE), KCNB1 (EIEE), KCNC1 (PME), KCNMA1 (GEPD), KCNQ2 (EIEE/BFNS), KCNQ3 (BFNS), KCNT1 (NFLE/EIEE)
       HCN channelHCN1 (EIEE)
       Calcium channelCACNA1A (EIEE), CACNA1H (CAE/IGE), CACNB4 (IGE/JME)
       Chloride channelCLCN2
      Description on phenotype was modified after retraction of the initial report.
      (IGE/JAE/JME)
       GABA-A receptorGABRA1 (EIEE/CAE/JME), GABRB1 (EIEE), GABRB3 (CAE​/EIEE), GABRD (GEFS+/IGE/JME), GABRG2 (GEFS+/FFS/CAE)
       NMDA receptorGRIN2A (FESD), GRIN2B (EIEE), GRIN2D (EIEE)
       Acetylcholine receptorCHRNA2 (NFLE), CHRNA4 (NFLE), CHRNB2 (NFLE)
      Enzyme/Enzyme modulator
       EnzymeAARS (EIEE), ALDH7A1 (EPD), ALG13 (EIEE), CDKL5 (EIEE), CERS1 (PME), CHD2 (COEE), CPA6 (FTLE/FFS), DNM1 (EIEE), EPM2A (PME), GNAO1 (EIEE), GUF1 (EIEE), ITPA (EIEE), NHLRC1 (PME), PLCB1 (EIEE), PNPO (PNPOD), PRDM8 (PME), SIK1 (EIEE), ST3GAL3 (EIEE), ST3GAL5 (AIES), UBA5 (EIEE), WWOX (EIEE)
       Enzyme modulatorARHGEF9 (EIEE), CSTB (PME), DOCK7 (EIEE), TBC1D24 (EIEE/FIME)
      Transporter/Receptor
       TransporterSLC1A2 (EIEE), SLC12A5 (EIEE/IGE), SLC13A5 (EIEE), SLC25A12 (EIEE), SLC25A22 (EIEE), SLC2A1 (IGE), SLC6A1 (MAE)
       ReceptorADRA2B (FAME), CASR (IGE), FRRS1L (EIEE), GPR98 (FFS), SCARB2 (PME)
      Cell adhesion moleculeCNTN2 (FAME), PCDH19 (EIEE)
      Signal transduction/moleculeEFHC1 (JAE/JME), FGF12 (EIEE)
      Membrane traffickingGOSR2 (PME), STX1B (GEFS+), STXBP1 (EIEE)
      Cytoskeletal proteinLMNB2 (PME), SPTAN1 (EIEE)
      Nucleic acid bindingEEF1A2 (EIEE), GUF1 (EIEE)
      UnclassifiedARV1 (EIEE), DEPDC5 (FFEVF), GAL (FTLE), KCTD7 (PME), LGI1 (FTLE), NECAP1 (EIEE), PRICKLE1 (PME), PRRT2 (BFIS), SZT2 (EIEE)
      Bold italics, with multiple functional classifications.
      AIES, Amish infantile epilepsy syndrome; BFIS, benign familial infantile seizures; BFNS, benign familial neonatal seizures; CAE, childhood absence epilepsy; COEE, childhood-onset epileptic encephalopathy; DS, Dravet syndrome; EIEE, early infantile epileptic encephalo-pathy; EPD, pyridoxine-dependent epilepsy; FAME, familial adult myoclonic epilepsy; FESD, focal epilepsy and speech disorder with or without mental retardation; FFEVF, familial focal epilepsy with variable foci; FFS, familial febrile seizures; FIME, familial infantile myoclonic epilepsy; FTLE, familial temporal lobe epilepsy; GEFS+, generalized epilepsy with febrile seizures plus; GEPD, generalized epilepsy and paroxysmal dyskinesia; IGE, idiopathic generalized epilepsy; JAE, juvenile absence epilepsy; JME, juvenile myoclonic epilepsy; MAE, myoclonic-atonic epilepsy; NFLE, nocturnal frontal lobe epilepsy; PME, progressive myoclonic epilepsy; PNPOD, pyridoxamine 5'-phosphate oxidase deficiency.
      a Description on phenotype was modified after retraction of the initial report.
      Table 2 shows that 17 epilepsy genes are involved in more than one epileptic phenotype. Theoretically, the impairment caused by mutations in a gene may vary in severity, thereby correlating with the severity of the phenotype. This is typically observed in epilepsies caused by SCN1A mutations which produce a spectrum of phenotypes ranging from the mild form of generalized epilepsies with febrile seizures plus, or pure febrile seizures [
      • Escayg A.
      • MacDonald B.T.
      • Meisler M.H.
      • Baulac S.
      • Huberfeld G.
      • An-Gourfinkel I.
      • et al.
      Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2.
      ,
      • Wallace R.H.
      • Scheffer I.E.
      • Barnett S.
      • Richards M.
      • Dibbens L.
      • Desai R.R.
      • et al.
      Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus.
      ], to the extremely severe form of the Dravet syndrome [
      • 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.
      ,
      • Ohmori I.
      • Ouchida M.
      • Ohtsuka Y.
      • Oka E.
      • Shimizu K.
      Significant correlation of the SCN1A mutations and severe myoclonic epilepsy in infancy.
      ], and there was a correlation between the genotypes or function alterations (functional-type or funotype) and phenotypes [
      • Meng H.
      • Xu H.Q.
      • Yu L.
      • Lin G.W.
      • He N.
      • Su T.
      • et al.
      The SCN1A mutation database: updating information and analysis of the relationships among genotype, functional alteration, and phenotype.
      ]. Similar correlations have been observed in epilepsies caused by mutations in KCNQ2 and GABRA1. For some genes, such as SCN2A and SCN8A, although mild and severe cases have been reported following their mutations, a correlation between genotype (or funotype) and phenotype has not been found yet. Thus, the pathogenic role played by these genes in epilepsy requires further investigation.

      3.2 Neurodevelopment-associated epilepsy genes

      In total, 73 genes were classified as neurodevelopment-associated epilepsy genes. Mutations in these genes produce gross neurodevelopmental malformations and epilepsy, which may vary in severity. Mutations in some genes, such as TSC1 and TSC2, cause the tuberous sclerosis, which may be accompanied by severe epilepsy [
      • Nellist M.
      • van den Heuvel D.
      • Schluep D.
      • Exalto C.
      • Goedbloed M.
      • Maat-Kievit A.
      • et al.
      Missense mutations to the TSC1 gene cause tuberous sclerosis complex.
      ,
      • Jansen A.C.
      • Sancak O.
      • D’Agostino M.D.
      • Badhwar A.
      • Roberts P.
      • Gobbi G.
      • et al.
      Unusually mild tuberous sclerosis phenotype is associated with TSC2 R905Q mutation.
      ]. Other genes, such as TUBB3 and WDR62, are associated with characteristic brain developmental malformations but infrequent epileptic seizures [
      • Poirier K.
      • Saillour Y.
      • Bahi-Buisson N.
      • Jaglin X.H.
      • Fallet-Bianco C.
      • Nabbout R.
      • et al.
      Mutations in the neuronal ss-tubulin subunit TUBB3 result in malformation of cortical development and neuronal migration defects.
      ,
      • Yu T.W.
      • Mochida G.H.
      • Tischfield D.J.
      • Sgaier S.K.
      • Flores-Sarnat L.
      • Sergi C.M.
      • et al.
      Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture.
      ].
      With the development of neuroimaging techniques, identification of the neurodevelopmental malformation provides critical evidences for the diagnosis and classification of the phenotype. We reviewed these genes according to the localization of brain malformations, which vary from focal (or multifocal) to general brain malformation. These brain malformations may be accompanied by physical or other systemic abnormalities (Table 3). It should be noted that gene mutations have also been identified in cases with subtle or undetectable malformations.
      Table 3Neurodevelopment-associated epilepsy genes.
      PhenotypeInheritanceGene
      Focal or multifocal brain malformation
      Grey matter
       HoloprosencephalyADPTCH1
      Seizures may be infrequent.
       Band-like calcification with simplified gyration and polymicrogyriaAROCLN
       Bilateral frontoparietal polymicrogyriaARGPR56
       Bilateral perisylvian polymicrogyriaUNGPR56
       Bilateral temporooccipital polymicrogyriaARFIG4
      Seizures may be infrequent.
       CK syndromeXLRNSDHL
       Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndromeADPIK3R2
      Seizures may be infrequent.
       Polymicrogyria with optic nerve hypoplasiaARTUBA8
       Rolandic epilepsy, speech dyspraxia, and mental retardationUNSRPX2
       Symmetric or asymmetric polymicrogyriaADTUBB2B
      Seizures may be infrequent.
       Periventricular heterotopiaXLDFLNA
       Periventricular heterotopia with microcephalyARARFGEF2
       Periventricular nodular heterotopiaADERMARD
      Seizures may be infrequent.
       Subcortical laminar heterotopiaXLDCX
      UNPAFAH1B1
      Seizures may be infrequent.
       Tuberous sclerosisADTSC1, TSC2
       Complex cortical dysplasia with other brain malformationsADKIF2A, KIF5C, TUBB2A, TUBB3
      Seizures may be infrequent.
      , TUBG1
      Seizures may be infrequent.
       Cortical dysplasia-focal epilepsy syndromeUNCNTNAP2
       Occipital cortical malformationsARLAMC3
       Pontocerebellar hypoplasiaARAMPD2, CLP1, EXOSC3
      Seizures may be infrequent.
      , PCLO
      Seizures may be infrequent.
      , SEPSECS, TSEN2
      Seizures may be infrequent.
      , TSEN54, VPS53
      UNTSEN15
       Mental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearanceXLROPHN1
      Seizures may be infrequent.
       Dentatorubro-pallidoluysian atrophyADATN1
       Idiopathic basal ganglia calcificationADSLC20A2
      Seizures may be infrequent.
      , XPR1
      Seizures may be infrequent.
      White matter and others
       Agenesis of the corpus callosum with peripheral neuropathyARSLC12A6
       Leukodystrophy and acquired microcephaly with or without dystoniaARPLEKHG2
      Seizures may be infrequent.
       Nonsyndromic hydrocephalusARCCDC88C, MPDZ
      Seizures may be infrequent.
       PorencephalyADCOL4A2
      Seizures may be infrequent.
       SchizencephalyUNEMX2
      General brain malformation
       LissencephalyADTUBA1A
      ARLAMB1, RELN
      XLARX, DCX
      UNPAFAH1B1
      Seizures may be infrequent.
       Lissencephaly with cerebellar hypoplasiaARCDK5
      Seizures may be infrequent.
       Lissencephaly with microcephalyARKATNB1, NDE1
       Epilepsy, hearing loss, and mental retardation syndromeARSPATA5
       Galloway-Mowat syndromeARWDR73
      Seizures may be infrequent.
       Mental retardation and microcephaly with pontine and cerebellar hypoplasiaXLDCASK
       Microcephaly-capillary malformation syndromeARSTAMBP
       Microcephaly, epilepsy, and diabetes syndromeARIER3IP1
       Microcephaly, seizures, and developmental delayARPNKP
       Microcephaly, short stature, and impaired glucose metabolismARPPP1R15B
      Seizures may be infrequent.
      , TRMT10A
       Microcephaly, short stature, and polymicrogyria with seizuresARRTTN
       Microcephaly with or without chorioretino-pathy, lymphedema, or mental retardationADKIF11
       Postnatal progressive microcephaly, seizures, and brain atrophyARMED17
       Primary microcephalyARANKLE2
      Seizures may be infrequent.
      , ASPM, CENPE
      Seizures may be infrequent.
      , CENPJ
      Seizures may be infrequent.
      , MFSD2A, SASS6
      Seizures may be infrequent.
       Primary microcephaly with or without cortical malformationsARWDR62
      Seizures may be infrequent.
       Progressive microcephaly with seizures and cerebral and cerebellar atrophyARQARS
       Seizures, cortical blindness, microcephaly syndromeARDIAPH1
       Macrocephaly, dysmorphic facies, and psychomotor retardationARHERC1
      Seizures may be infrequent.
       Polyhydramnios, megalencephaly, and symptomatic epilepsyUNSTRADA
       X-linked epilepsy with variable learning disabilities and behavior disordersXLD, XLRSYN1
       Psychomotor retardation, epilepsy, and craniofacial dysmorphismARSNIP1
      Bold italics, with multiple epilepsy phenotypes. ARX is associated with early infantile epileptic encephalopathy (XLR) and lissencephaly (XL). RELN is associated with familial temporal lobe epilepsy (AD) and lissencephaly (AR).
      AD, autosomal dominant; AR, autosomal recessive; UN, unknown; XL, X-linked; XLD, X-linked dominant; XLR, X-linked recessive.
      a Seizures may be infrequent.
      From the gene-function point of view (Table 4), enzyme/enzyme modulator genes represent a large fraction of neurodevelopment-associated epilepsy genes (24/73), suggesting that these genes play a significant role in neurodevelopment and epileptogenesis. Genes encoding cytoskeletal molecules appeared also frequently (15/73). The remaining genes are involved in cell adhesion, extracellular matrix, membrane structure, membrane trafficking, or other unknown functions. In contrast, we did not come across any ion-channel gene. These data may further our knowledge on the pathogenic mechanisms of neurodevelopment and epilepsies.
      Table 4Functional categories of the neurodevelopment-associated epilepsy genes.
      Encoded protein functionGene
      Enzyme/Enzyme modulator
       EnzymeAMPD2, CASK, CDK5, EXOSC3, FIG4, HERC1, KATNB1, NSDHL, PAFAH1B1, PIK3R2, PNKP, QARS, SEPSECS, STAMBP, TRMT10A, TSEN15, TSEN2, TSEN54
       Enzyme modulatorARFGEF2, CCDC88C, OPHN1, PLEKHG2, PPP1R15B, TSC2
      Transporter/Receptor
       TransporterMFSD2A, SLC12A6, SLC20A2, SPATA5
       ReceptorGPR56, PTCH1, XPR1
      Cell adhesion moleculeCNTNAP2
      Extracellular matrixCOL4A2, LAMB1, LAMC3, RELN
      Membrane structureOCLN
      Membrane traffickingSYN1
      Cytoskeletal proteinCENPE, CENPJ, DCX, DIAPH1, FLNA, KIF11, KIF2A, KIF5C, PCLO, TUBA1A, TUBA8, TUBB2A, TUBB2B, TUBB3, TUBG1
      Nucleic acid bindingARX, CLP1, EMX2
      UnclassifiedANKLE2, ASPM, ATN1, ERMARD, IER3IP1, MED17, MPDZ, NDE1, RTTN, SASS6, SNIP1, SRPX2, STRADA, TSC1, VPS53, WDR62, WDR73

      3.3 Epilepsy-related genes

      From the OMIM database, 536 genes were recognized as epilepsy-related genes. These genes are associated with diseases presenting gross physical, or other systemic, abnormalities that are accompanied by epilepsy or seizures. For example, the FMR1 gene defect causes Fragile X Syndrome which may be accompanied by seizures. However, the distinct features of Fragile X Syndrome are the intellectual disability, behavioral abnormalities, and physical alterations (such as an elongated face and large, or protruding, ears).
      Epileptic seizures may occur in numerous genetic diseases (Table 5) including those that directly affect the cerebral neurons, such as the neuronal ceroid lipofuscinosis, in which epileptic seizure is a prominent feature; and those that may be indirectly related to brain function, such as the spinal muscular atrophy, in which epileptic seizure is inconstant. The characteristic clinical features of these disorders, beside epilepsy, usually provide useful clues for the clinical diagnosis and prompt for further genetic tests.
      Table 5Epilepsy-related genes.
      PhenotypeInheritanceGene
      Circulation disorder
       Cavernous malform-ationsADCCM1, KRIT1
       Long QT syndromeADCALM2, KCNQ1, KCNJ5
      UNCAV3
       Moyamoya diseaseARGUCY1A3
      UNRNF213
       Others (cerebral amyl-oid angiopathy, etc.)ADCOL4A1, PRNP, PROS1
      ARCTC1, F2, JAM3
      Cognitive disorder
       Alzheimer diseaseADAPP, PSEN1, PSEN2
       Angelman syndromeUNUBE3A (IC)
       AutismADCHD8
      XLRTMLHE
      UNRPL10, SLC9A9
       Fragile X syndromeXLDFMR1
       Frontotemporal dementiaADMAPT
       Mental retardationADARID1A, ARID1B, ASXL1, AUTS2, BRAF, DEAF1, DYNC1H1, GNB1, HIVEP2, KAT6A, KIAA0442, KIF1A, MBD5, MED13L, MYT1L, NONO, PPP2R1A, PPP2R5D, PURA, SETBP1, SMARCA2, SMARCA4, SMARCB1, SMARCE1, SYNGAP1, TCF4, ZEB2
      ARANK3, ERCC6, FMN2, FTO, GRIK2, HERC2, KPTN, LMAN2L, MAN1B1, MED25, METTL23, NRXN1, PGAP1, PIGG, PUS3, SOBP, TRAPPC9
      XLDIQSEC2, SLC9A6, SYP, USP9X, ZDHHC15
      XLRAP1S2, ATP6AP2, CLIC2, CUL4B, DLG3, FGD1, GRIA3, HCFC1, IL1RAPL1, KDM5C, KIF4A, MECP2, MID2, PAK3, PHF6, RAB39B, SMS, TAF1, THOC2, UBE2A
      UNCACNG2, COL4A3BP, DYRK1A, FTSJ1, GATAD2B, GDI1, GPT2, GRIN1, MEF2C (IC), SHROOM4
       Others (McLeod syndrome, progressive encephalopathy, etc.)ADRAI1 (IC), SERPINI1
      ARBSCL2
      XLXK
      UNMTOR
      Developmental disorder (with physical malformation)
       Congenital disorder of glycosylationARALG1, ALG11, ALG2, ALG3, ALG6, CAD, COG4, COG6, DOLK, DPAGT1, DPM1, DPM2, MOGS, MPDU1, NGLY1, RFT1, SLC39A8, STT3A, STT3B
      XLD, SMoSLC35A2
      XLRSSR4
      UNALG12, ALG9, COG7, COG8
       Joubert syndromeARAHI1, CC2D2A, CSPP1
      UNOFD1
       MicrophthalmiaADBMP4, OTX2, RBP4, SOX2
      XLNAA10
       Multiple congenital anomalies-hypotonia-seizures syndromeARPIGN
      AD, SMu; ARPIGT
      XLRPIGA
       Muscular dystrophyARCHKB, LAMA2, TRAPPC11
       Muscular dystrophy-dystroglycanopathyARB3GNT1, B4GAT1, FKTN, GMPPB, POMGNT1, POMK, POMT1, POMT2
       NeurofibromatosisADNF1
       NeuropathyADDNMT1, SPTLC2
      ARABHD12
       Rett syndromeUNFOXG1 (IC)
       Spinal muscular atrophy with progressive myo-clonic epilepsyARASAH1
       Sturge–Weber syndromeUNGNAQ
       Zellweger syndromeARPEX2
      UNPEX13, PEX14, PEX19, PEX3
       Others (craniosynost-osis, thanatophoric dysplasia, etc.)ADACTB, ACTG1, ACVR1, ADNP, DNMT3A, EFTUD2, EHMT1 (IC), FAM111A, FGFR2, FGFR3, GATA6, HNF1B, KCNH1, KCNJ6, KMT2A, MAF, MAGEL2, MAPRE2, MARCA2, MSX2, NOTCH1, NSD1, POGZ, PTEN, PUF60, SATB2, SETD2, SOX5, ZSWIM6
      ARAGPS, ALDH18A1 (IC), AP3D1, ARNT2, ATP6V0A2, BRAT1, C12orf57, C19orf61, CCDC88A, CEP164, CLPP, COL18A1, CRB2, CRLF1, DHCR24, DOCK6, EPG5, EXT2, FAT4, GNPAT, GPSM2, GPX4, LRP2, MKS1, NANS, NIN, PARN, PEX5, PIGL, RAB18, RAPSN, ROGDI, SLC33A1, SLC35A3, TELO2, XPNPEP3
      XLDAMER1, DXS423E, NDUFB11, NHS, SMC1A
      XLRBCAP31, CHRDL1, DKC1, EBP, MBTPS2, PQBP1, RBM10, ZC4H2
      UNCEP290, CHN1, KRAS, NDN (IC), NRAS, SHANK3 (IC), SNRPN (IC)
      Inflammation and immune disorder
       Herpes simplex ence-phalitisADIRF3
      UNTICAM1, TRAF3
       ImmunodeficiencyARBCL10, CORO1A, IFNAR2, ISG15, ORAI1, PGM3, PRKDC, STAT1, STAT2
      XLRATP6AP1
       Inflammatory disorderADIFIH1, NOD2
      ARCD59, PSMB8
       Others (candidiasis, neutropenia, etc.)ADRANBP2
      ARCARD9, DOCK8, FADD, HAX1
      AD, ARCPT2
      Metabolic disorder
       AciduriaARACADSB, AUH, C2orf25, CLPB, CTH, D2HGDH, DHTKD1, DPYS, GLYCTK, MMAA, MMADHC, MTR, SLC25A1
      UNACSF3, IDH2
       Amino acid metabolic disturbanceARAASS, ALDH4A1, AMT, ARG1, GCH1, GLDC, GLUL, LIAS, PRODH, QDPR, SLC25A15
       Coenzyme Q10 deficiencyARCOQ2, COQ4, COQ6, COQ8A, COQ9, PDSS2
       Combined oxidative phosphorylation deficiencyARCARS2, EARS2, FARS2, GFM1, GTPBP3, MRPS22, MTFMT, MTO1, NARS2, RMND1, TXN2, VARS2
      XLRAIFM1
       Diabetes mellitusADABCC8, KCNJ11
      UNZFP57
       Enzymatic deficiencyADATP1A2, RYR1
      ARABAT, ACADS, ACOX1, ACY1, ADK, ADSL, AMACR, ASNS, ATIC, BCKDHA, CPS1, DHFR, DLD, DPYD, FAR1, HIBCH, MCCC1, MCCC2, MLYCD, MTHFR, NADK2, OPLAH, PC, PDHX, PDX1, PHGDH, PSAP, PSAT1, PSPH, SCO2, SLC25A20, UPB1
      XLDHSD17B10, PDHA1
      XLRGK, MAOA, NDP, OTC, PGK1
      UNBCKDK, HADHA, HMGCS2, NAT8L, PEX7, POMC
       Folate malabsorptionARSLC46A1
       Folate transport deficiencyARFOLR1
       Glycogen storage diseaseARAGL, GYS1
       Hormone metabolism dysfunctionADCACNA1D, GLI2, PROK2, THRB
      ARMCM8, MRAP
      AD, ARHESX1
      XLRAVPR2
      XLANOS1
      UNFGF8
       Hyperphosphatasia with mental retardation syndromeARPGAP2, PGAP3, PIGO, PIGV, PIGW, PIGY
       HypocalcemiaADGNA11
       HypoglycemiaADAKT2, GCK, INSR
       HypomagnesemiaARTRPM6
      AD, ARCNNM2
      UNEGF
       HypoparathyroidismADPTH
       Leigh syndromeARLRPPRC
      AR, MiNDUFA2, NDUFAF6, NDUFS4, NDUFS8
       Lipid storage disorderARNPC1, NPC2
       Menkes diseaseXLRATP7A
       Mitochondrial disease (progressive external ophthalmoplegia with mitochondrial DNA deletions, etc.)ADPOLG2
      ARATP5A1, ATPAF2, BCS1L, BOLA3, BRP44L, C10orf2, FBXL4, MPC1, PNPLA8, POLG, RRM2B, RTN4IP1, SDHD, SUCLA2, TMEM70, UQCC2
      AR, MiAPOPT1, COX10, COX6B1, COX8A, FASTKD2, PET100
      AR, XLD, MiFOXRED1, NDUFA1, NDUFAF3, NDUFV1, NUBPL
       MucopolysaccharidosisARHGSNAT
      XLRIDS
       Neuronal ceroid lipofuscinosisADDNAJC5
      ARCLN3, CLN5, CLN6, CLN8, CTSD, CTSF, GRN, MFSD8, PPT1, TPP1
       Thiamine metabolism dysfunction syndromeARSLC19A3, TPK1
       Vitamin D-dependent ricketsARCYP27B1
       Others (brain iron accumulation, Salla disease, etc.)ADANKH, COL3A1, DNM1L, TTR
      ARARHGDIA, CYB5R3, ECM1, ETFDH, ETHE1, GAMT, GBA, HADHB, HEXA, HSD17B4, KCNJ10, LARS2, MOCS2, PIGM, PLA2G6, SLC17A5, TANGO2
      AD, ARFTL, SLC16A1
      XLDWDR45
      XLRSLC6A8
      UNGPHN
      Movement disorder
       Cerebellar ataxiaADCAMTA1
      ARSLC9A1
       DyskinesiaARPDE10A
       DystoniaADSGCE
      ARACO2, CRYAB, NALCN, TBCK, UNC80
      AD, ARGLRA1, SPR
       Episodic ataxiaADKCNA1
      UNSLC1A3
       Episodic hemiplegiaADATP1A3
       Huntington diseaseADHTT
       Parkinson diseaseADLRRK2
      ARDNAJC6, SYNJ1
       Spastic ataxiaARAFG3L2, SACS
       Spastic paraplegiaADNIPA1
      ARAP4B1, AP4E1, AP4S1, ERLIN2, GJC2, HACE1, TECPR2, ZFYVE26
      XLRPLP1
       Spastic quadriplegiaARADD3, ELOVL4, GAD1, SLC1A4
       Spinocerebellar ataxiaADATXN10, ITPR1, TBP
      ARANO10, GRM1, RUBCN, SNX14, SYT14, TDP2
      UNTDP1
      Myelinating disorder
       Alexander diseaseADGFAP
       Krabbe diseaseARGALC
       LeukodystrophyADTUBB4A
      ARAIMP1, ARSA, HSPD1, POLR3B, VPS11
       LeukoencephalopathyADCSF1R
      ARDARS2, EIF2B1, HEPACAM, MLC1, RNASET2
      Neoplastic disorder
       GlioblastomaARBRCA2
      AD, autosomal dominant; AR, autosomal recessive; IC, isolated cases; Mi, mitochondrial; SMo, somatic mosaicism; SMu, somatic mutation; UN, unknown; XL, X-linked; XLD, X-linked dominant; XLR, X-linked recessive.

      3.4 Potential epilepsy-associated genes

      We found 247 additional genes by crosschecking our findings with those from the HGMD and the EpilepsyGene databases and 37 more genes by searching through recent publications (Table 6). These genes are reported to be potentially associated with epilepsy; however, they are currently not present in the OMIM database. Their associations with epilepsy warrant further verification in most of the cases. For instance, CUX1 and MCM9 were listed in the EpilepsyGene database. Mutations in CUX1, MCM9, and KCNT1 were identified in a patient with malignant migrating partial seizures of infancy. KCNT1 is an epilepsy gene and the KCNT1 mutation (c.2800G>A, p.Ala934Thr) identified in this patient has been experimentally proved to cause functional alternations [
      • Barcia G.
      • Fleming M.R.
      • Deligniere A.
      • Gazula V.R.
      • Brown M.R.
      • Langouet M.
      • et al.
      De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy.
      ]. Thus, the role of CUX1 and MCM9 in epilepsy has been questioned. In contrast, mutations in some genes, such as SCN3A, GABRA6, and KCNH5, have been repeatedly reported in patients with epilepsy [
      • Vanoye C.G.
      • Gurnett C.A.
      • Holland K.D.
      • George Jr., A.L.
      • Kearney J.A.
      Novel SCN3A variants associated with focal epilepsy in children.
      ,
      • Chen Y.J.
      • Shi Y.W.
      • Xu H.Q.
      • Chen M.L.
      • Gao M.M.
      • Sun W.W.
      • et al.
      Electrophysiological differences between the same pore region mutation in SCN1A and SCN3A.
      ,
      • Dibbens L.M.
      • Harkin L.A.
      • Richards M.
      • Hodgson B.L.
      • Clarke A.L.
      • Petrou S.
      • et al.
      The role of neuronal GABA(A) receptor subunit mutations in idiopathic generalized epilepsies.
      ,
      • Hernandez C.C.
      • Gurba K.N.
      • Hu N.
      • Macdonald R.L.
      The GABRA6 mutation, R46W, associated with childhood absence epilepsy, alters 6beta22 and 6beta2 GABA(A) receptor channel gating and expression.
      ,
      • Veeramah K.R.
      • Johnstone L.
      • Karafet T.M.
      • Wolf D.
      • Sprissler R.
      • Salogiannis J.
      • et al.
      Exome sequencing reveals new causal mutations in children with epileptic encephalopathies.
      ,
      • Yang Y.
      • Vasylyev D.V.
      • Dib-Hajj F.
      • Veeramah K.R.
      • Hammer M.F.
      • Dib-Hajj S.D.
      • et al.
      Multistate structural modeling and voltage-clamp analysis of epilepsy/autism mutation Kv10.2-R327H demonstrate the role of this residue in stabilizing the channel closed state.
      ], and functional alterations induced by these mutations have been experimentally confirmed [
      • Chen Y.J.
      • Shi Y.W.
      • Xu H.Q.
      • Chen M.L.
      • Gao M.M.
      • Sun W.W.
      • et al.
      Electrophysiological differences between the same pore region mutation in SCN1A and SCN3A.
      ,
      • Hernandez C.C.
      • Gurba K.N.
      • Hu N.
      • Macdonald R.L.
      The GABRA6 mutation, R46W, associated with childhood absence epilepsy, alters 6beta22 and 6beta2 GABA(A) receptor channel gating and expression.
      ,
      • Yang Y.
      • Vasylyev D.V.
      • Dib-Hajj F.
      • Veeramah K.R.
      • Hammer M.F.
      • Dib-Hajj S.D.
      • et al.
      Multistate structural modeling and voltage-clamp analysis of epilepsy/autism mutation Kv10.2-R327H demonstrate the role of this residue in stabilizing the channel closed state.
      ].
      Table 6Potential epilepsy-associated genes.
      Encoded protein functionGene
      Ion channel
       Sodium channelSCN3A, SCN4A, SCN5A
       Potassium channelKCNAB1, KCNAB2, KCNC3, KCND2, KCND3, KCNE1, KCNH2, KCNH5, KCNJ2, KCNMB3, KCNN3, KCNV2, KCTD3
       HCN channelHCN2, HCN4
       Calcium channelCACNA1G, CACNA2D1, CACNA2D2, RYR3, TRPM1
       Chloride channelCLCN4, CLCN6
       GABA-A receptorGABRA6, GABRB2
       NMDA receptorGRIK1, GRINA
       Acetylcholine receptorCHRFAM7A, CHRNA7, CHRNB3
      Enzyme/Enzyme modulator
       EnzymeACMSD, ACOT7, ADAM22, AKT3, CBL, CHD1L, CHD3, CHD4, COX1, COX3, CP, CSNK1G1, CYP26C1, DGKD, DNM3, FASN, FBXO28, GBE1, HCK, HDAC4, HECW2, HS2ST1, HUWE1, INPP4A, KARS, KDM6A, KIAA1456, MAGI2, MAN2A2, MANBA, MAPK10, MCM9, ME2, MPP7, MRI1, MTMR11, ND1, ND4, ND5, NEDD4, NEDD4L, NEU1, OPA1, PARK2, PHF8, PIGQ, PNPT1, PRKX, PTPN23, SGK223, ST8SIA2, STK11, TK2, TNK2, TRIM8, TRMT44, UBR5, WHSC1, ZMYND8
       Enzyme modulatorARHGEF15, ELMO1, FARP2, FSTL5, NOL3, NPRL2, NPRL3, PPP1R3C, RANGAP1, RAPGEF6, SRGAP2
      Transporter/receptor
       TransporterAAAS, ATP13A2, ATP6, ATP6V0C, ATP8, ATP8A2, NIPA2, OCA2, SLC1A1, SLC25A2, SLC26A1, SLC30A3, SLC4A10, SLC4A3, SLC6A3, SLC6A4, SLC7A11, SLC8A1, SLCO1B7, TAP1
       ReceptorADORA2A, AGTR2, CD46, CRHR1, CXCR4, ENG, EPHA5, EPHB2, ERBB4, FLT4, GABBR1, GABBR2, HTR1A, HTR2A, IL27RA, LPHN2, NPC1L1, NR2F1, OPRM1, OR10H2, PLXNB2, RORB, RTN4R, TRNR1, TSPAN7
      Transmembrane receptor regulatory/adaptorDLG2, GIPC1
      Extracellular matrixCOL2A1, COL6A2, COL6A3, HSPG2, MATN4, NID1, TNFAIP6
      Cell adhesion moleculeCELSR3, CHL1, CTNND2, L1CAM, NLGN1, PCDH12, PCDH15, PCDH7, PCDHB13, PCDHB4, PCDHG
      Signaling moleculeBDNF, BMP5, CRH, IL10, IL1B, IL1RN, IL6, NRG2, NRG3, PDYN, SEMA5B
      Signal transductionCALN1, CLSTN1
      Membrane structureGJD2, LOR, PMP22
      Membrane traffickingEXOC6B, NAPB, SEC24D, SNAP25, SV2A, SYN2, SYT2, TSNARE1, VPS35
      Surfactant proteinSUCO
      Cytoskeletal proteinDMD, GAS2L2, HIP1, KIF3C, MYH14, MYH6, MYO9B, NEB, SVIL, TBCD, TUBA3E
      Nucleic acid bindingBRD2, CELF4, CENPW, CREBBP, CUX1, DMBX1, EFTUD2, EIF2C4, EIF3E, GMEB2, HNRNPH1, HNRNPU, HOXD, INO80, JRK, KLF13, MED12, MLLT3, MSC, MYOCD, PHOX2B, RBFOX1, RBFOX3, RBPJ, RFX3, SCA2, SCNM1, SETD5, SON, THAP1, YAP1, ZBTB18, ZMYND11, ZNF12, ZNF182, ZNF44
      ChaperoneTBCD, TOR1A
      Transfer/carrierAPOE4, CYTB, KPNA7, WDR19
      Defence/immuneC3, IGSF8
      UnclassifiedBRWD3, BSN, C16orf62, C18orf25, C7orf55, DIP2C, FLG, GRIP1, HEG1, ITGB1BP1, KIAA2022, LRFN5, NCKAP5, NELL1, NGFRAP1, NKAIN3, NOL11, PIK3AP1, PODXL, PRICKLE2, PRRC2B, RB1, RD3, SEZ6, SHANK1, SKI, SLC7A6OS, SQSTM1, ST5, ST7, STYXL1, TBL1XR1, TENM2, TMEM139, TSPYL4, TTN, YWHAE, ZFYVE20
      Bold italics, with multiple functional classifications.

      4. Discussion

      Here, we review all genes potentially associated with epilepsy, and present a summary of these genes according to the manifestation of epilepsy in the phenotype. These genes include epilepsy genes, neurodevelopment-associated epilepsy genes, and epilepsy-related genes. These integrated data represent a framework of epilepsy-associated genes that may be used for the following: (1) considering genetic tests in clinical practice and (2) evaluating the results of these tests. However, we must acknowledge that an endeavour such as this runs the risk of being incomplete, since there continue to be identification of novel epilepsy-associated genes in the following days.
      Eighty-four genes have been considered as epilepsy genes. However, it should be noted that although these genes are associated with epilepsies, the pathogenic role played by each gene may differ according to the phenotype. For instance, both SCN1A and SCN9A are reported to be associated with the Dravet syndrome. Mutations in SCN1A are responsible for approximately 70–80% of the cases with Dravet syndrome [
      • Meng H.
      • Xu H.Q.
      • Yu L.
      • Lin G.W.
      • He N.
      • Su T.
      • et al.
      The SCN1A mutation database: updating information and analysis of the relationships among genotype, functional alteration, and phenotype.
      ,
      • 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.
      ,
      • Marini C.
      • Scheffer I.E.
      • Nabbout R.
      • Suls A.
      • De Jonghe P.
      • Zara F.
      • et al.
      The genetics of Dravet syndrome.
      ], and the genotype (funotype)-phenotype correlations have been documented [
      • Meng H.
      • Xu H.Q.
      • Yu L.
      • Lin G.W.
      • He N.
      • Su T.
      • et al.
      The SCN1A mutation database: updating information and analysis of the relationships among genotype, functional alteration, and phenotype.
      ]. In contrast, SCN9A may play a minor role and was suggested as a modifier gene in Dravet syndrome [
      • Singh N.A.
      • Pappas C.
      • Dahle E.J.
      • Claes L.R.
      • Pruess T.H.
      • De Jonghe P.
      • et al.
      A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome.
      ]. Generally, an epileptic syndrome may have several genetic causes. Idiopathic epilepsies are believed to be caused by genetic abnormalities. Mutations in several genes have been identified in idiopathic epilepsies, such as GABRG2, GABRB3, CACNA1H, and GABRA1 in childhood absence epilepsy. However, the pathogenic role of each gene in idiopathic epilepsy warrants further experimental and clinical studies. From a practical point of view, except few genes like SCN1A, the frequency of gene mutation in an epileptic syndrome was not determined for most of the epilepsy genes. On the other hand, it has been frequently observed that an epilepsy gene may lead to several phenotypes, i.e., a spectrum of phenotype. Theoretically, due to the distinct function of the gene, phenotypes within the spectrum would share features in common, typically shown in the spectrum of epilepsy caused by SCN1A mutations. SCN1A mutations are associated with Dravet syndrome, partial epilepsy with antecedent febrile seizures, and generalized epilepsies with febrile seizures plus. The antecedent febrile seizure is the common feature in most of the cases and is a critical clue in clinical diagnosis and management [
      • Meng H.
      • Xu H.Q.
      • Yu L.
      • Lin G.W.
      • He N.
      • Su T.
      • et al.
      The SCN1A mutation database: updating information and analysis of the relationships among genotype, functional alteration, and phenotype.
      ,
      • Liao W.P.
      • Shi Y.W.
      • Long Y.S.
      • Zeng Y.
      • Li T.
      • Yu M.J.
      • et al.
      Partial epilepsy with antecedent febrile seizures and seizure aggravation by antiepileptic drugs: associated with loss of function of Na(v) 1.1.
      ].
      Seventy-three genes have been considered as neurodevelopment-associated genes and 536 genes have been listed as epilepsy-related genes. The apparent neurodevelopmental malformation and gross physical or systemic abnormalities accompanied would provide critical evidences for the diagnosis and clues for designing cost-effective genetic-testing strategy for a specific target patient population. Two hundred and eighty-four genes are putatively associated with epilepsy. Although further verifications are required, new epilepsy genes are expected to be identified. The present summary of gene functions and their associations with epilepsy will serve as the basis for considering future studies, and it will further our understanding of the underlying genetic mechanisms of epilepsy.

      Conflicts of interest

      All authors declare that they have no conflicts of interest concerning this article.

      Acknowledgements

      This work was supported by Omics-based precision medicine of epilepsy being entrusted by Key Research Project of the Ministry of Science and Technology of China . (Grant No. 2016YFC0904400 ), the National Natural Science Foundation of China (grant Nos. 81271434 , 81301107 , 81571273 , 81571274 , 81501124 and 81501125 ), the Natural Science Foundation of Guangdong Province (grant Nos. 2014A030310094 and 2014A030313489 ), Science and Technology Project of Guangdong Province (grant No. 2013B051000084 ) Department of Education of Guangdong Province (grant Nos. 2013CXZDA022 , 2013KJCX0156 and 2012KJCX009 ), Foundation for High-level Talents in Higher Education of Guangdong (grant No. 2013-167 ), Yangcheng Scholar Research Project of Guangzhou Municipal College (grant Nos. 12A016S and 12A017G ), Science and Technology Project of Guangzhou (grant Nos. 2014J4100069 , 201508020011 , 201604020161 , and 201607010002 ), the Cultivation and Innovation Fund of Jinan University (grant No. 21615334 ) and Collaborative Innovation Center for Neurogenetics and Channelopathies . The funders had no role in study design, data collection and analysis, and decision to publish or preparation of the manuscript.

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