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Revista médica del Hospital General de México

Print version ISSN 0185-1063

Online version ISSN 2524-177X

Rev. med. Hosp. Gen. Méx.  vol. 82n. 1
https://doi.org/10.24875/HGMX.M19000001

Review articles

Genomic studies in epilepsy

Article Indicators
Guzmán-Jiménez, Diana E.12

Flores-Ramírez, Erika L.23

Velasco-Monroy, Ana L.2*

Author affiliation
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  • 1Programa de Doctorado en Ciencias Biomédicas, UNAM, Mexico City
  • 2Clinica de Epilepsia, Unidad de Neurocirugía Funcional y Estereotaxia, Unidad de Neurología y Neurocirugía, Hospital General de México, Mexico City
  • 3Estudiante de Servivio Social en Investigación, Universidad Nacional Autónoma de Guadalajara, Jalisco. Mexico
Author notes
*Correspondence: Ana Luisa Velasco-Monroy E-mail: analuisav@yahoo.com
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Sociedad Médica del Hospital General de Mexico. Published by Permanyer. This is an open ccess article under the CC BY-NC-ND license

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Abstract

Epilepsy is a progressive and disabling disease if not diagnosed early; for this reason, it has been the subject of research, specially in cases with idiopathic etiology. Approximately between 1 and 2% of the world population have epilepsy. In Mexico the prevalence is from 10 to 20 patients per 1000 inhabitants. Lately, the scientific community has been trying to create, adapt, and use biomolecular tools to study its pathophysiology so that, hopefully, in a near future we are able to intervene in the natural history of this disease. The aim of this work is to cite evidence about some of the molecular biology techniques in order to support and encourage investment in neurogenomical research; as a necessary tool in the study of epilepsy.

Key words:
Epilepsy, Biomolecular Tools, Neurogenomics

Introduction

The International League Against Epilepsy (ILAE) defines an epileptic seizure as the occurrence of signs and/or symptoms due to an excessive synchronous or asynchronous abnormal neuronal activity, and epilepsy as a disease characterized by the long-term predisposition to generate epileptic seizures, as well as, by the neurobiological, cognitive, psychological, and social consequences of this condition1.

In the world, there are >50 million people suffering from epilepsy, of which 80% live in developing countries with a prevalence of 7-14 per 1000 inhabitants, unlike the developed countries with a proportion of 4-10 per 1000 habitants2.

In Mexico, a prevalence of 10-20 per 1000 habitants has been found; therefore, it can be estimated that there are approximately 1-2 million Mexicans affected3.

Etiologically, epilepsy can be classified into the following groups: symptomatic or secondary (where there is a known cause, such as tumor, neuroinfection, and congenital brain malformation), idiopathic (when genetic factors are suspected, inherited, or de novo, etc.), and cryptogenic (type of epilepsy in which it cannot be associated to a certain cause)4. Around 20-30% of epilepsies are caused by acquired conditions and 70-80% are related to one or more genetic factors5.

Epilepsy is considered a public health problem, due to its high morbidity and psychosocial repercussions (stigmatization or rejection) and economic (unemployment, pharmacological, and hospitalization expenses); therefore, it should be a reason for interest, investment, and research to understand the disease and provide the best care to this sector of the population. Considering the proportion of epilepsy related to genetic factors, 5 it is crucial to know the clinical, physiological, and genomic tools used in the diagnosis in this type of patients.

Since the publication in 1951 in JAMA by the epileptologist William G. Lennox, it was possible to confirm the importance of the genetic causes in some types of epilepsy, observed in their studies in twins6. Later, Watson and Crick (1953) propose the helical structure, antiparallel, and complementary to DNA7, researchers have used these principles for the development of molecular technology to understand and analyze the genetic material of all kinds of organisms, including humans, interest in the study of inheritance and genes, using genomics (a discipline that deals with the study of genomes, genes, and their functions, as well as related biotechnological techniques)8.

Advances in genomic technology are providing tools for the study of genetic factors that may be involved with different types of epilepsy. Some of the main types of studies used in epilepsy research are described below: full genome-wide association studies (GWAS), sequencing, next-generation sequencing (NGS), sequencing of whole genome (whole genome sequencing/[WGS]), complete exome sequencing (whole exome sequencing/[WES]), chromosomal microarrays (RNA and DNA microarrays) by comparative genomic hybridization (CGH) to detect copy number variations (CNVs), insertions and deletions, single-nucleotide polymorphisms (SNPs), or point mutations, (Fig. 1).

Thumbnail
Variations in the genome of a single base. Variants of a single nucleotide within a DNA sequence can be classified as SNP< 1% or as a point mutation <1% according to their frequency in the study population.
Figure 1
Variations in the genome of a single base. Variants of a single nucleotide within a DNA sequence can be classified as SNP< 1% or as a point mutation <1% according to their frequency in the study population.

Full Genome Association Studies (GWAS)

In genetic epidemiology, a complete genome association study (GWA) uses high-throughput technologies to analyze hundreds of thousands of SNPs (SNPs, generally referring to a single-base variant in the human genome) and relates them to measurable traits, as well as with various clinical conditions. These are studies designed to identify common genetic variants between two or more populations that contribute to a risk of disease9.

As an example, in 2014, the ILAE published a meta-analysis of 12 cohorts where they performed a complete genome association on 8696 patients with epilepsy and 26,157 controls. They found association of risk in the loci 2q24.3 (p=8.71×10−10) that involves the gene SCN1A and in the loci 4p15.1 (p=5 44×10−9) that involves the PCDH7 gene in patients with focal and generalized epilepsy. For patients with generalized epilepsy at the 2p16.1 loci (p=9.99×10−9), which implicate the VRK2 or FANCL genes, they could not determine an SNP with statistical significance related to focal epilepsy10. Feenstra et al.11 studied through GWA children with febrile seizures as an adverse effect after the administration of the triple viral vaccine (rubella, measles, and mumps), children who did not have febrile seizures after the vaccine and finally children without a history of febrile seizures as controls. They found two risk loci related to febrile seizures after vaccination rs273259 (p=5.9×10−12 and p=1.2×10−9) involving the gene IFI44L and rs1318653 (p=9.6×10−11 and p=1.6×10−9) that involves the CD46 gene, with p values against the controls and against children who did not have febrile seizures after the vaccine, respectively. On the other hand, they found four risk loci for febrile seizures, in general, two were in known genes related to epilepsy (SCN1A and SCN2A).

Copy Number Variations (CNVs)

CNVs are defined as a DNA segment equal to or >1 kb whose number of copies is variable (duplicated or deleted) when compared to a reference genome (Fig. 2).

Thumbnail
Copy number variations (CNVs). Variation in the number of copies, by loss (deletion) or gain (duplication) of a DNA segment greater than one kilobase with respect to a reference genome.
Figure 2
Copy number variations (CNVs). Variation in the number of copies, by loss (deletion) or gain (duplication) of a DNA segment greater than one kilobase with respect to a reference genome.

CNVs are an important source of normal genetic variation (in a frequency >1%), but some may participate as risk factors or causes of disease5,12. CNVs can be detected with DNA microarrays by means of CGH, array CGH, (Fig. 3)

Thumbnail
Next-generation sequencing (NGS) determines the order of the nucleotides of a specific sequence. It can be used to determine only the coding part of a sequence (exome) or the whole sequence (genome).
Figure 3
Next-generation sequencing (NGS) determines the order of the nucleotides of a specific sequence. It can be used to determine only the coding part of a sequence (exome) or the whole sequence (genome).

Some rare CNVs (frequency <1%) involve genes from known diseases and may be related to 5-10% in cases of childhood epilepsy13,14. Helbig et al. reported the role of CNVs in patients with epilepsy, finding 88 rare NVs in 71 patients (31.8%) >100 kb related to the disease15.

In general, research in generalized and focal epilepsy has identified recurrent microdeletions in up to 3% of patients with idiopathic generalized epilepsy and 1% focal epilepsy. The microdeletions in the chromosomal regions 15q13.3 and 16p13.11 are the most frequently identified variants16,17.

Next Generation Sequencing (NGS)

DNA sequencing refers to the determination of the order of the nucleotides of a given sequence, from some base pairs (bp) to the sequence of complete genomes. The NGS, also called mass sequencing in parallel, means that millions of small DNA fragments (around 100 bp) can be sequenced at the same time18.

At present, two types of sequencing are performed for the study of epilepsy: complete genome sequencing and complete exome sequencing (Fig. 3).

Complete Genome Sequencing (WGS)

It refers to the determination of the order of the nucleotides of the whole genome (both the coding and non-coding sequences) which covers around 3000 million bp19.

Complete Exome Sequencing (WES)

This technique allows exploring 180,000 exons or coding regions (more or less 30 million bp), which corresponds to approximately 1% of the human genome20, it is estimated that 85% of the variations related to hereditary diseases are found in the exome18.

Helbig et al. evaluated the performance of exome sequencing as a diagnostic method in patients with epilepsy, finding 38.2% positive results compared to controls with p=0.004 value, concluding that this technique is a useful diagnostic tool, especially in severe epilepsy of early onset21.

In the past 10 years, the advancement of complete genome sequencing or exome techniques has allowed the identification of new genes and genetic variants involved in family epilepsies, severe epilepsies, and epileptic encephalopathies, which has had an important impact in the diagnosis of this disease. The current rate in the diagnosis of epilepsy by NGS ranges from 20% to 30% and specifically with WES is approximately 25%22.

Candidate Genes Related to Epilepsy

Some of the major genes involved in generalized epilepsy are described below:

SCN1A codes for the alpha-1 subunit of the voltage-dependent sodium channel. The transmembrane alpha subunit forms the central pore of the channel. This ion channel is critical for the generation and propagation of action potentials. The channel responds to the voltage difference across the cell membrane to create a pore that allows sodium ions to pass through the membrane. The influx of sodium creates an action potential, which is critical for signaling within the brain. Mutations of loss of function cause a reduction of sodium currents and alteration of the signaling of the hippocampal GABAergic interneurons. Allelic variants of this gene are associated with generalized epilepsy with febrile seizures and epileptic encephalopathy. In 70-90% of cases, Dravet syndrome is caused by a de novo mutation in SCN1A, which often leads to a non-functional protein23,24.

SCN2A encodes the alpha-II subunit of the voltage-dependent sodium channel and is found in the initial segment of the axon, nonsense mutations are observed in patients with epileptic encephalopathies where their expression is reduced on the cell surface, resulting in a net loss of function. This mutation is related to four different phenotypes such as benign neonatal and infantile epilepsy, autism and intellectual disability, infantile spasms, and early-onset epileptic encephalopathies including Ohtahara syndrome and severe neonatal epilepsy. All phenotypes within the SCN2A spectrum include cognitive disturbances, seizures, and movement disorders23,24.

CACNA1A codes for the alpha-1 subunit of voltage-dependent calcium channels and mediates the entry of calcium ions into excitable cells; it is also included calcium-dependent processes including muscle contraction, hormone release, and neurotransmitter release. Mutations in this gene are related to episodic ataxias, spinocerebellar degeneration, and familial hemiplegic migraine, generalized epilepsies such as absences or Dravet syndrome, and tonic paroxysms23,24.

Regarding focal epilepsy, the main candidate genes are described below:

GRIN2A encodes the alpha-2 subunit of the glutamate receptor N-methyl-D-aspartate, it is involved in long-term potentiation, an activity-dependent increase in the efficiency of synaptic transmission; the interruption of this gene is associated with the disorder of focal rolandic epilepsy, atypical benign partial epilepsy, Landau-Kleffner syndrome, and some learning disorders23,24.

DEPDC5 codes for a member of the IML1 family of proteins involved in G-protein signaling pathways (mTORC1) and regulates cell growth by detecting nutrient availability; inhibition of mTOR can cause cortical dysplasia at variable sites. Mutations in this gene have been related to focal epilepsy of variable foci, nocturnal frontal lobe dominant epilepsy, and temporal mesial lobe family epilepsy23,24.

LGI1 gene codes for a member of the superfamily of proteins rich in leucine (glioma rich in inactivated leucine), can regulate the activity of voltage-dependent potassium channels, and is involved in the regulation of neuronal growth and cell survival. This gene is rearranged as the result of translocations in glioblastoma cell lines. Mutations in this gene are related to lateral temporal epilepsy23,24.

The discovery of mutations in specific genes (encoders for ion channels expressed in brain neurons, neurotransmitter receptors, or molecules with assumed functions in intercellular communication) has allowed to corroborate the suspicions that the physiopathological bases of this disease seem to be related with alterations in the electrical type processes, especially those that cause alterations in the stability of the membranes25,26.

The table summarizes some of the candidate genes related to epilepsy, discovered by sequencing, association studies, DNA microarrays, etc. (Supplementary Table 1).

One of the main goals in the molecular research of epilepsy is to provide personalized treatment, and some data are beginning to emerge that this may be possible, in 2014, the abnormal gain of the function of the KCNQ1 gene that codes for member 1 of the Q subfamily of potassium channels dependent on filtration and reverts with quinidine27. On the other hand, personalized therapy with memantine or topiramate was also proposed in two patients with early-onset epileptic encephalopathy with mutation in the GRIN2A gene28.

It is important to take into account the genetic factors related to the disease when deciding the treatment of the patient, especially if the treatment is a surgical procedure. Skjei et al. published a series of cases in which they describe the clinical and histopathological characteristics in six patients with refractory epilepsy and mutations in the SCN1A gene undergoing focal cortical resection. In all cases, patients were refractory to the surgical procedure; it was observed mild diffuse malformations of cortical development in four of six patients concluding that cortical resection may not be effective in patients with this mutation and with the neuropathological changes mentioned29.

New approaches for the treatment of epilepsy are under development, experimental research based on viral vectors, genetic opto tools involving the use of light at wavelengths of 280-570 nm, to control the activity of ion channels in rhodopsin and halorhodopsin in hippocampal neurons, dentate gyrus, and cerebellum, which activate or inhibit a neuron and even several conglomerates of neuronal networks that allow a control of neuronal electrical activity and cell graft techniques in animal models; all of them are new techniques used for a future to prevent the disease or to provide the best treatment to this type of patients30,31.

Conclusion

Epilepsy is considered a disease of complex inheritance, the main difficulties associated with the study of complex diseases are incomplete penetrance, genetic heterogeneity, and polygenic (or multifactorial) inheritance32. Therefore, it is not yet clear what is the role of inheritance and other genetic factors in epileptogenesis. There is currently a project called Phenotype/Epilepsy Genotype EPGP: the Epilepsy Phenome/Genome Project; it is a large-scale project involving 27 centers in the United States, Australia, Argentina and Canada with the aims of analyzing the detailed phenotype of patients, determining the genotype and discovering new genes. Genetics and genomics in epilepsy is an open field of research that has had a great break in the last 15 years, which has solved many of the cases that were previously classified as of unknown cause, however, there is still a long way to go.

References

  • 1
    Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report:a practical clinical definition of epilepsy. Epilepsia. 2014;55:475-82. Links
  • 2
    OMS, Organización Mundial de la Salud. Available from:http://www.who.int/mediacentre/factsheets/fs999/en/. [Last accessed on 2016 Jul 17]. Links
  • 3
    Programa Prioritario de Epilepsia. Frecuencia en México. Available from:http://www.epilepsiamexico.gob.mx/info-pacientes/frecuencia.htm. [Last accessed on 2016 Jul 17]. Links
  • 4
    Epilpsy Society. Available from:https://www.epilepsysociety.org.uk/causes-epilepsy#.V8MuCSYoDtQ. [Last accessed on 2016 Jul 17]. Links
  • 5
    Myers CT, Mefford HC. Advancing epilepsy genetics in the genomic era. Genome Med. 2015;7:91. Links
  • 6
    Lennox WG. The heredity of epilepsy as told by relatives and twins. J Am Med Assoc. 1951;146:529-36. Links
  • 7
    Watson JD, Crick FH. Molecular structure of nucleic acids;A structure for deoxyribose nucleic acid. Nature. 1953;171:737-8. Links
  • 8
    Genomics and World Health:report of the Advisory Committee on Health Research. Geneva:WHO;2002. Available from:http://www.who.int/genomics/geneticsVSgenomics/en/. [Last accessed on 2016 Jul 17]. Links
  • 9
    Wan X, Yang C, Yang Q, et al. Predictive rule inference for epistatic interaction detection in genome-wide association studies. Bioinformatics. 2010;26:30-7. Links
  • 10
    International League Against Epilepsy Consortium on Complex Epilepsies. Electronic address:epilepsy-austin@unimelb.edu.au. Genetic determinants of common epilepsies:a meta-analysis of genome-wide association studies. Lancet Neurol. 2014;13:893-903. Links
  • 11
    Feenstra B, Pasternak B, Geller F, et al. Common variants associated with general and MMR vaccine-related febrile seizures. Nat Genet. 2014;46:1274-82. Links
  • 12
    Hastings PJ, Lupski JR, Rosenberg SM, Ira G. Mechanisms of change in gene copy number. Nat Rev Genet. 2009;10:551-64. Links
  • 13
    Olson H, Shen Y, Avallone J, et al. Copy number variation plays an important role in clinical epilepsy. Ann Neurol. 2014;75:943-58. Links
  • 14
    Mefford HC, Yendle SC, Hsu C, et al. Rare copy number variants are an important cause of epileptic encephalopathies. Ann Neurol. 2011;70:974-85. Links
  • 15
    Helbig I, Swinkels ME, Aten E, et al. Structural genomic variation in childhood epilepsies with complex phenotypes. Eur J Hum Genet. 2014;22:896-901. Links
  • 16
    Mefford HC, Muhle H, Ostertag P, et al. Genome-wide copy number variation in epilepsy:novel susceptibility loci in idiopathic generalized and focal epilepsies. PLoS Genet. 2010;6:e1000962. Links
  • 17
    Heinzen EL, Radtke RA, Urban TJ, et al. Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes. Am J Hum Genet. 2010;86:707-18. Links
  • 18
    Jiménez-Escrig A, Gobernado I, Sánchez-Herranz A. Secuenciación de genoma completo:un salto cualitativo en los estudios genéticos. Rev Neurol. 2012;54:692-8. Links
  • 19
    Martin HC, Kim GE, Pagnamenta AT, et al. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Hum Mol Genet. 2014;23:3200-11. Links
  • 20
    Kumar A, Turner E, Shendure J. Targeted capture and massively parallel sequencing of the human exome. J Investig Med. 2010;58:123. Links
  • 21
    Helbig KL, Farwell Hagman KD, Shinde DN, et al. Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet Med. 2016;18:898-905. Links
  • 22
    Møller RS, Dahl HA, Helbig I. The contribution of next generation sequencing to epilepsy genetics. Expert Rev Mol Diagn. 2015;15:1531-8. Links
  • 23
    The ILAE Genetics Commission Blog. Beyond the Ion Channel. Available from:http://www.epilepsygenetics.net/the-epilepsiome/scn1a-this-is-what-you-need-to-know/. [Last accessed on 2016 Mar 17]. Links
  • 24
    Gene Cards. Available from:http://www.genecards.org/, 2016. [Last accessed on 2016 Mar 04]. Links
  • 25
    Baulac S. Genetics advances in autosomal dominant focal epilepsies:focus on DEPDC5. Prog Brain Res. 2014;213:123-39. Links
  • 26
    Labate A, Gambardella A, Andermann E, et al. Benign mesial temporal lobe epilepsy. Nat Rev Neurol. 2011;7:237-40. Links
  • 27
    Milligan CJ, Li M, Gazina EV, et al. KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann Neurol. 2014;75:581-90. Links
  • 28
    Pierson TM, Yuan H, Marsh ED, et al. GRIN2A mutation and early-onset epileptic encephalopathy:personalized therapy with memantine. Ann Clin Transl Neurol. 2014;1:190-8. Links
  • 29
    Skjei KL, Church EW, Harding BN, et al. Clinical and histopathological outcomes in patients with SCN1A mutations undergoing surgery for epilepsy. J Neurosurg Pediatr. 2015;16:668-74. Links
  • 30
    Kovac S, Walker MC. Recent advances in epilepsy. J Neurol. 2014;261:837-41. Links
  • 31
    Ortiz-Vilchis CM. Modelos experimentales en optogenética y su aplicación en enfermedades neurodegenerativas motoras. Rev Med Inv. 2015;3:107-68. Links
  • 32
    Lopes-Cendes I, Ribeiro PA. Aspectos genéticos de las epilepsias:una visión actualizada. Rev Méd Clín Las Condes. 2013;24:909-14. Links

Supplementary material references

  • 1
    de Ligt J, Willemsen MH, van Bon BW, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012;367:1921-9. Links
  • 2
    Dimassi S, Labalme A, Ville D, et al. Whole-exome sequencing improves the diagnosis yield in sporadic infantile spasm syndrome. Clin Genet. 2016;89:198-204. Links
  • 3
    Epi4K Consortium, Epilepsy Phenome/Genome Project, Allen AS, et al. De novo mutations in epileptic encephalopathies. Nature. 2013;501:217-21. Links
  • 4
    Michaud JL, Lachance M, Hamdan FF, et al. The genetic landscape of infantile spasms. Hum Mol Genet. 2014;23:4846-58. Links
  • 5
    Møller RS, Dahl HA, Helbig I. The contribution of next generation sequencing to epilepsy genetics. Expert Rev Mol Diagn 2015;15:1531-8. Links
  • 6
    Timal S, Hoischen A, Lehle L, et al. Gene identification in the congenital disorders of glycosylation Type I by whole-exome sequencing. Hum Mol Genet. 2012;21:4151-61. Links
  • 7
    Harvey K, Duguid IC, Alldred MJ, et al. The GDP-GTP exchange factor collybistin:an essential determinant of neuronal gephyrin clustering. J Neurosci. 2004;24:5816-26. Links
  • 8
    Lesca G, Till M, Labalme A, Vallee D, et al. De novo xq11.11 microdeletion including ARHGEF9 in a boy with mental retardation, epilepsy, macrosomia, and dysmorphic features. Am J Med Genet A. 2011;155A:1706-11. Links
  • 9
    Lesca G, Depienne C. Epilepsy genetics:the ongoing revolution. Rev Neurol. 2015;171:539-57. Links
  • 10
    Shimojima K, Sugawara M, Shichiji M, et al. Loss-of-function mutation of collybistin is responsible for X-linked mental retardation associated with epilepsy. J Hum Genet. 2011;56:561-5. Links
  • 11
    Bruyere H, Lewis S, Wood S, MacLeod PJ, Langlois S. Confirmation of linkage in X-linked infantile spasms (West syndrome) and refinement of the disease locus to xp21.3-xp22.1. Clin Genet. 1999;55:173-81. Links
  • 12
    Claes S, Devriendt K, Lagae L, et al. The X-linked infantile spasms syndrome (MIM 308350) maps to xp11.4-xpter in two pedigrees. Ann Neurol. 1997;42:360-4. Links
  • 13
    Feinberg AP, Leahy WR. Infantile spasms:case report of sex-linked inheritance. Dev Med Child Neurol. 1977;19:524-6. Links
  • 14
    Fullston T, Brueton L, Willis T, et al. Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C>G/p.Y27X). Eur J Hum Genet. 2010;18:157-62. Links
  • 15
    Giordano L, Sartori S, Russo S, et al. Familial ohtahara syndrome due to a novel ARX gene mutation. Am J Med Genet A. 2010;152A:3133-7. Links
  • 16
    Kato M, Das S, Petras K, et al. Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. Hum Mutat. 2004;23:147-59. Links
  • 17
    Kato M, Saitoh S, Kamei A, et al. A longer polyalanine expansion mutation in the ARX gene causes early infantile epileptic encephalopathy with suppression-burst pattern (Ohtahara syndrome). Am J Hum Genet. 2007;81:361-6. Links
  • 18
    Poeta L, Fusco F, Drongitis D, et al. A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARX. Am J Hum Genet. 2013;92:114-25. Links
  • 19
    Proud VK, Levine C, Carpenter NJ. New X-linked syndrome with seizures, acquired micrencephaly, and agenesis of the corpus callosum. Am J Med Genet. 1992;43:458-66. Links
  • 20
    Strømme P, Mangelsdorf ME, Shaw MA, et al. Mutations in the human ortholog of aristaless cause X-linked mental retardation and epilepsy. Nat Genet. 2002;30:441-5. Links
  • 21
    Strømme P, Sundet K, Mørk C, et al. X linked mental retardation and infantile spasms in a family:new clinical data and linkage to xp11.4-xp22.11. J Med Genet. 1999;36:374-8. Links
  • 22
    Turner G, Partington M, Kerr B, Mangelsdorf M, Gecz J. Variable expression of mental retardation, autism, seizures, and dystonic hand movements in two families with an identical ARX gene mutation. Am J Med Genet. 2002;112:405-11. Links
  • 23
    Chan YC, Burgunder JM, Wilder-Smith E, et al. Electroencephalographic changes and seizures in familial hemiplegic migraine patients with the CACNA1A gene S218L mutation. J Clin Neurosci. 2008;15:891-4. Links
  • 24
    Chioza B, Wilkie H, Nashef L, et al. Association between the alpha(1a) calcium channel gene CACNA1A and idiopathic generalized epilepsy. Neurology. 2001;56:1245-6. Links
  • 25
    Holtmann M, Opp J, Tokarzewski M, Korn-Merker E. Human epilepsy, episodic ataxia Type 2, and migraine. Lancet. 2002;359:170-1. Links
  • 26
    Jouvenceau A, Eunson LH, Spauschus A, et al. Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel. Lancet. 2001;358:801-7. Links
  • 27
    Kors EE, Melberg A, Vanmolkot KR, et al. Childhood epilepsy, familial hemiplegic migraine, cerebellar ataxia, and a new CACNA1A mutation. Neurology. 2004;63:1136-7. Links
  • 28
    Chen Y, Lu J, Pan H, et al. Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann Neurol. 2003;54:239-43. Links
  • 29
    Heron SE, Khosravani H, Varela D, et al. Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants. Ann Neurol. 2007;62:560-8. Links
  • 30
    Khosravani H, Altier C, Simms B, et al. Gating effects of mutations in the cav3.2 T-type calcium channel associated with childhood absence epilepsy. J Biol Chem. 2004;279:9681-4. Links
  • 31
    Khosravani H, Bladen C, Parker DB, et al. Effects of cav3.2 channel mutations linked to idiopathic generalized epilepsy. Ann Neurol. 2005;57:745-9. Links
  • 32
    Vitko I, Chen Y, Arias JM, et al. Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel. J Neurosci. 2005;25:4844-55. Links
  • 33
    Mefford HC, Yendle SC, Hsu C, et al. Rare copy number variants are an important cause of epileptic encephalopathies. Ann Neurol. 2011;70:974-85. Links
  • 34
    Vergult S, Dheedene A, Meurs A, et al. Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability. Eur J Hum Genet. 2015;23:628-32. Links
  • 35
    Archer HL, Evans J, Edwards S, et al. CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients. J Med Genet. 2006;43:729-34. Links
  • 36
    Elia M, Falco M, Ferri R, et al. CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy. Neurology. 2008;71:997-9. Links
  • 37
    Bartnik M, Derwińska K, Gos M, et al. Early-onset seizures due to mosaic exonic deletions of CDKL5 in a male and two females. Genet Med. 2011;13:447-52. Links
  • 38
    Erez A, Patel AJ, Wang X, et al. Alu-specific microhomology-mediated deletions in CDKL5 in females with early-onset seizure disorder. Neurogenetics. 2009;10:363-9. Links
  • 39
    Kalscheuer VM, Tao J, Donnelly A, et al. Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation. Am J Hum Genet. 2003;72:1401-11. Links
  • 40
    Nectoux J, Heron D, Tallot M, Chelly J, Bienvenu T. Maternal origin of a novel C-terminal truncation mutation in CDKL5 causing a severe atypical form of rett syndrome. Clin Genet. 2006;70:29-33. Links
  • 41
    Nemos C, Lambert L, Giuliano F, et al. Mutational spectrum of CDKL5 in early-onset encephalopathies:a study of a large collection of French patients and review of the literature. Clin Genet. 2009;76:357-71. Links
  • 42
    Rademacher N, Hambrock M, Fischer U, et al. Identification of a novel CDKL5 exon and pathogenic mutations in patients with severe mental retardation, early-onset seizures and rett-like features. Neurogenetics. 2011;12:165-7. Links
  • 43
    Rosas-Vargas H, Bahi-Buisson N, Philippe C, et al. Impairment of CDKL5 nuclear localisation as a cause for severe infantile encephalopathy. J Med Genet. 2008;45:172-8. Links
  • 44
    Russo S, Marchi M, Cogliati F, et al. Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes. Neurogenetics. 2009;10:241-50. Links
  • 45
    Saletti V, Canafoglia L, Cambiaso P, et al. A CDKL5 mutated child with precocious puberty. Am J Med Genet A. 2009;149A:1046-51. Links
  • 46
    Scala E, Ariani F, Mari F, et al. CDKL5/STK9 is mutated in rett syndrome variant with infantile spasms. J Med Genet. 2005;42:103-7. Links
  • 47
    Tao J, Van Esch H, Hagedorn-Greiwe M, et al. Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation. Am J Hum Genet. 2004;75:1149-54. Links
  • 48
    Van Esch H, Jansen A, Bauters M, Froyen G, Fryns JP. Encephalopathy and bilateral cataract in a boy with an interstitial deletion of xp22 comprising the CDKL5 and NHS genes. Am J Med Genet A. 2007;143:364-9. Links
  • 49
    Weaving LS, Christodoulou J, Williamson SL, et al. Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. Am J Hum Genet. 2004;75:1079-93. Links
  • 50
    Carvill GL, Heavin SB, Yendle SC, et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet. 2013;45:825-30. Links
  • 51
    Chénier S, Yoon G, Argiropoulos B, et al. CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems. J Neurodev Disord. 2014;6:9. Links
  • 52
    Galizia EC, Myers CT, Leu C, et al. CHD2 variants are a risk factor for photosensitivity in epilepsy. Brain. 2015;138:1198-207. Links
  • 53
    Liu JC, Ferreira CG, Yusufzai T. Human CHD2 is a chromatin assembly ATPase regulated by its chromo-and DNA-binding domains. J Biol Chem. 2015;290:25-34. Links
  • 54
    Lund C, Brodtkorb E, Øye AM, Røsby O, Selmer KK. CHD2 mutations in lennox-gastaut syndrome. Epilepsy Behav. 2014;33:18-21. Links
  • 55
    Rauch A, Wieczorek D, Graf E, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability:an exome sequencing study. Lancet. 2012;380:1674-82. Links
  • 56
    Suls A, Jaehn JA, Kecskés A, et al. De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with dravet syndrome. Am J Hum Genet. 2013;93:967-75. Links
  • 57
    Thomas RH, Zhang LM, Carvill GL, et al. CHD2 myoclonic encephalopathy is frequently associated with self-induced seizures. Neurology. 2015;84:951-8. Links
  • 58
    Trivisano M, Striano P, Sartorelli J, et al. CHD2 mutations are a rare cause of generalized epilepsy with myoclonic-atonic seizures. Epilepsy Behav. 2015;51:53-6. Links
  • 59
    Dibbens LM, Mullen S, Helbig I, et al. Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy:precedent for disorders with complex inheritance. Hum Mol Genet. 2009;18:3626-31. Links
  • 60
    Helbig I, Mefford HC, Sharp AJ, et al. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet. 2009;41:160-2. Links
  • 61
    Peñagarikano O, Abrahams BS, Herman EI, et al. Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell. 2011;147:235-46. Links
  • 62
    Strauss KA, Puffenberger EG, Huentelman MJ, et al. Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med. 2006;354:1370-7. Links
  • 63
    Alakurtti K, Weber E, Rinne R, et al. Loss of lysosomal association of cystatin B proteins representing progressive myoclonus epilepsy, EPM1, mutations. Eur J Hum Genet. 2005;13:208-15. Links
  • 64
    Bespalova IN, Adkins S, Pranzatelli M, Burmeister M. Novel cystatin B mutation and diagnostic PCR assay in an unverricht-lundborg progressive myoclonus epilepsy patient. Am J Med Genet. 1997;74:467-71. Links
  • 65
    de Haan GJ, Halley DJ, Doelman JC, et al. Univerricht-lundborg (sic) disease:underdiagnosed in the Netherlands. Epilepsia. 2004;45:1061-3. Links
  • 66
    Di Giaimo R, Riccio M, Santi S, et al. New insights into the molecular basis of progressive myoclonus epilepsy:a multiprotein complex with cystatin B. Hum Mol Genet. 2002;11:2941-50. Links
  • 67
    Lafrenière RG, Rochefort DL, Chrétien N, et al. Unstable insertion in the 5'flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy Type 1, EPM1. Nat Genet. 1997;15:298-302. Links
  • 68
    Lalioti MD, Mirotsou M, Buresi C, et al. Identification of mutations in cystatin B, the gene responsible for the unverricht-lundborg type of progressive myoclonus epilepsy (EPM1). Am J Hum Genet. 1997;60:342-51. Links
  • 69
    Mazarib A, Xiong L, Neufeld MY, et al. Unverricht-lundborg disease in a five-generation arab family:instability of dodecamer repeats. Neurology. 2001;57:1050-4. Links
  • 70
    Pennacchio LA, Lehesjoki AE, Stone NE, et al. Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1) Science. 1996;271:1731-4. Links
  • 71
    Virtaneva K, D'Amato E, Miao J, et al. Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1. Nat Genet. 1997;15:393-6. Links
  • 72
    Baulac S, Ishida S, Marsan E, et al. Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations. Ann Neurol. 2015;77:675-83. Links
  • 73
    Berkovic SF, Serratosa JM, Phillips HA, et al. Familial partial epilepsy with variable foci:clinical features and linkage to chromosome 22q12. Epilepsia. 2004;45:1054-60. Links
  • 74
    Callenbach PM, van den Maagdenberg AM, Hottenga JJ, et al. Familial partial epilepsy with variable foci in a dutch family:clinical characteristics and confirmation of linkage to chromosome 22q. Epilepsia. 2003;44:1298-305. Links
  • 75
    Dibbens LM, de Vries B, Donatello S, et al. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet. 2013;45:546-51. Links
  • 76
    Ishida S, Picard F, Rudolf G, et al. Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nat Genet. 2013;45:552-5. Links
  • 77
    Klein KM, O'Brien TJ, Praveen K, et al. Familial focal epilepsy with variable foci mapped to chromosome 22q12:expansion of the phenotypic spectrum. Epilepsia. 2012;53:e151-5. Links
  • 78
    Martin C, Meloche C, Rioux MF, et al. A recurrent mutation in DEPDC5 predisposes to focal epilepsies in the french-canadian population. Clin Genet. 2014;86:570-4. Links
  • 79
    Picard F, Baulac S, Kahane P, et al. Dominant partial epilepsies. A clinical, electrophysiological and genetic study of 19 European families. Brain. 2000;123 (Pt 6):1247-62. Links
  • 80
    Picard F, Makrythanasis P, Navarro V, et al. DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy. Neurology. 2014;82:2101-6. Links
  • 81
    Scheffer IE, Heron SE, Regan BM, et al. Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Ann Neurol. 2014;75:782-7. Links
  • 82
    Scheffer IE, Phillips HA, O'Brien CE, et al. Familial partial epilepsy with variable foci:a new partial epilepsy syndrome with suggestion of linkage to chromosome 2. Ann Neurol. 1998;44:890-9. Links
  • 83
    Xiong L, Labuda M, Li DS, et al. Mapping of a gene determining familial partial epilepsy with variable foci to chromosome 22q11-q12. Am J Hum Genet. 1999;65:1698-710. Links
  • 84
    Epilepsy Phenome/Genome Project Epi4K Consortium. Copy number variant analysis from exome data in 349 patients with epileptic encephalopathy. Ann Neurol. 2015;78:323-8. Links
  • 85
    Boumil RM, Letts VA, Roberts MC, et al. A missense mutation in a highly conserved alternate exon of dynamin-1 causes epilepsy in fitful mice. PLoS Genet. 2010;6:e1001046. Links
  • 86
    Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015;519:223-8. Links
  • 87
    Dhindsa RS, Bradrick SS, Yao X, et al. Epileptic encephalopathy-causing mutations in DNM1 impair synaptic vesicle endocytosis. Neurol Genet. 2015;1:e4. Links
  • 88
    EuroEPINOMICS-RES Consortium, Epilepsy Phenome/Genome Project, Epi4K Consortium. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet. 2014;95:360-70. Links
  • 89
    Perrault I, Hamdan FF, Rio M, et al. Mutations in DOCK7 in individuals with epileptic encephalopathy and cortical blindness. Am J Hum Genet. 2014;94:891-7. Links
  • 90
    Carvill GL, Weckhuysen S, McMahon JM, et al. GABRA1 and STXBP1:novel genetic causes of dravet syndrome. Neurology. 2014;82:1245-53. Links
  • 91
    Cossette P, Liu L, Brisebois K, et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet. 2002;31:184-9. Links
  • 92
    Ding L, Feng HJ, Macdonald RL, et al. GABA(A) receptor alpha1 subunit mutation A322D associated with autosomal dominant juvenile myoclonic epilepsy reduces the expression and alters the composition of wild type GABA(A) receptors. J Biol Chem. 2010;285:26390-405. Links
  • 93
    Lachance-Touchette P, Brown P, Meloche C, et al. Novel ?1 and ?2 GABAA receptor subunit mutations in families with idiopathic generalized epilepsy. Eur J Neurosci. 2011;34:237-49. Links
  • 94
    Maljevic S, Krampfl K, Cobilanschi J, et al. A mutation in the GABA(A) receptor alpha(1)-subunit is associated with absence epilepsy. Ann Neurol. 2006;59:983-7. Links
  • 95
    Tanaka M, Olsen RW, Medina MT, et al. Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy. Am J Hum Genet. 2008;82:1249-61. Links
  • 96
    Urak L, Feucht M, Fathi N, Hornik K, Fuchs K. A GABRB3 promoter haplotype associated with childhood absence epilepsy impairs transcriptional activity. Hum Mol Genet. 2006;15:2533-41. Links
  • 97
    Audenaert D, Schwartz E, Claeys KG, et al. A novel GABRG2 mutation associated with febrile seizures. Neurology. 2006;67:687-90. Links
  • 98
    Baulac S, Huberfeld G, Gourfinkel-An I, et al. First genetic evidence of GABA(A) receptor dysfunction in epilepsy:a mutation in the gamma2-subunit gene. Nat Genet. 2001;28:46-8. Links
  • 99
    Chaumont S, AndréC, Perrais D, Boué-Grabot E, et al. Agonist-dependent endocytosis of ?-aminobutyric acid Type A (GABAA) receptors revealed by a ?2(R43Q) epilepsy mutation. J Biol Chem. 2013;288:28254-65. Links
  • 100
    Chiu C, Reid CA, Tan HO, et al. Developmental impact of a familial GABAA receptor epilepsy mutation. Ann Neurol. 2008;64:284-93. Links
  • 101
    Frugier G, Coussen F, Giraud MF, et al. A gamma 2(R43Q) mutation, linked to epilepsy in humans, alters GABAA receptor assembly and modifies subunit composition on the cell surface. J Biol Chem. 2007;282:3819-28. Links
  • 102
    Harkin LA, Bowser DN, Dibbens LM, et al. Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus. Am J Hum Genet. 2002;70:530-6. Links
  • 103
    Kananura C, Haug K, Sander T, et al. A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions. Arch Neurol. 2002;59:1137-41. Links
  • 104
    Kang JQ, Shen W, Macdonald RL. Why does fever trigger febrile seizures?GABAA receptor gamma2 subunit mutations associated with idiopathic generalized epilepsies have temperature-dependent trafficking deficiencies. J Neurosci. 2006;26:2590-7. Links
  • 105
    Sancar F, Czajkowski C. A GABAA receptor mutation linked to human epilepsy (gamma2R43Q) impairs cell surface expression of alphabetagamma receptors. J Biol Chem. 2004;279:47034-9. Links
  • 106
    Tan HO, Reid CA, Single FN, et al. Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy. Proc Natl Acad Sci U S A. 2007;104:17536-41. Links
  • 107
    Wallace RH, Marini C, Petrou S, et al. Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet. 2001;28:49-52. Links
  • 108
    Nakamura K, Kodera H, Akita T, et al. De novo mutations in GNAO1, encoding a g?o subunit of heterotrimeric G proteins, cause epileptic encephalopathy. Am J Hum Genet. 2013;93:496-505. Links
  • 109
    Carvill GL, Regan BM, Yendle SC, et al. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet. 2013;45:1073-6. Links
  • 110
    Endele S, Rosenberger G, Geider K, et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet. 2010;42:1021-6. Links
  • 111
    Lesca G, Rudolf G, Bruneau N, et al. GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nat Genet. 2013;45:1061-6. Links
  • 112
    Lemke JR, Lal D, Reinthaler EM, et al. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet. 2013;45:1067-72. Links
  • 113
    Scheffer IE, Jones L, Pozzebon M, et al. Autosomal dominant rolandic epilepsy and speech dyspraxia:a new syndrome with anticipation. Ann Neurol. 1995;38:633-42. Links
  • 114
    Nava C, Dalle C, Rastetter A, et al. De novo mutations in HCN1 cause early infantile epileptic encephalopathy. Nat Genet. 2014;46:640-5. Links
  • 115
    Bassi MT, Balottin U, Panzeri C, et al. Functional analysis of novel KCNQ2 and KCNQ3 gene variants found in a large pedigree with benign familial neonatal convulsions (BFNC). Neurogenetics. 2005;6:185-93. Links
  • 116
    Berkovic SF, Kennerson ML, Howell RA, et al. Phenotypic expression of benign familial neonatal convulsions linked to chromosome 20. Arch Neurol. 1994;51:1125-8. Links
  • 117
    Biervert C, Schroeder BC, Kubisch C, et al. A potassium channel mutation in neonatal human epilepsy. Science. 1998;279:403-6. Links
  • 118
    Biervert C, Steinlein OK. Structural and mutational analysis of KCNQ2, the major gene locus for benign familial neonatal convulsions. Hum Genet. 1999;104:234-40. Links
  • 119
    Borgatti R, Zucca C, Cavallini A, et al. A novel mutation in KCNQ2 associated with BFNC, drug resistant epilepsy, and mental retardation. Neurology. 2004;63:57-65. Links
  • 120
    Dedek K, Fusco L, Teloy N, Steinlein OK. Neonatal convulsions and epileptic encephalopathy in an italian family with a missense mutation in the fifth transmembrane region of KCNQ2. Epilepsy Res. 2003;54:21-7. Links
  • 121
    del Giudice EM, Coppola G, Scuccimarra G, et al. Benign familial neonatal convulsions (BFNC) resulting from mutation of the KCNQ2 voltage sensor. Eur J Hum Genet. 2000;8:994-7. Links
  • 122
    Heron SE, Cox K, Grinton BE, et al. Deletions or duplications in KCNQ2 can cause benign familial neonatal seizures. J Med Genet. 2007;44:791-6. Links
  • 123
    Saitsu H, Kato M, Koide A, et al. Whole exome sequencing identifies KCNQ2 mutations in ohtahara syndrome. Ann Neurol. 2012;72:298-300. Links
  • 124
    Singh NA, Charlier C, Stauffer D, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet. 1998;18:25-9. Links
  • 125
    Weckhuysen S, Mandelstam S, Suls A, et al. KCNQ2 encephalopathy:emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol. 2012;71:15-25. Links
  • 126
    Wuttke TV, Jurkat-Rott K, Paulus W, et al. Peripheral nerve hyperexcitability due to dominant-negative KCNQ2 mutations. Neurology. 2007;69:2045-53. Links
  • 127
    Yang WP, Levesque PC, Little WA, et al. Functional expression of two kvLQT1-related potassium channels responsible for an inherited idiopathic epilepsy. J Biol Chem. 1998;273:19419-23. Links
  • 128
    Zimprich F, Ronen GM, Stögmann W, et al. Andreas rett and benign familial neonatal convulsions revisited. Neurology. 2006;67:864-6. Links
  • 129
    Barcia G, Fleming MR, Deligniere A, et al. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet. 2012;44:1255-9. Links
  • 130
    Derry CP, Heron SE, Phillips F, et al. Severe autosomal dominant nocturnal frontal lobe epilepsy associated with psychiatric disorders and intellectual disability. Epilepsia. 2008;49:2125-9. Links
  • 131
    Heron SE, Smith KR, Bahlo M, et al. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet. 2012;44:1188-90. Links
  • 132
    Ishii A, Shioda M, Okumura A, et al. A recurrent KCNT1 mutation in two sporadic cases with malignant migrating partial seizures in infancy. Gene. 2013;531:467-71. Links
  • 133
    Ohba C, Kato M, Takahashi S, et al. Early onset epileptic encephalopathy caused by de novo SCN8A mutations. Epilepsia. 2014;55:994-1000. Links
  • 134
    Vanderver A, Simons C, Schmidt JL, et al. Identification of a novel de novo p.Phe932Ile KCNT1 mutation in a patient with leukoencephalopathy and severe epilepsy. Pediatr Neurol. 2014;50:112-4. Links
  • 135
    Chabrol E, Popescu C, Gourfinkel-An I, et al. Two novel epilepsy-linked mutations leading to a loss of function of LGI1. Arch Neurol. 2007;64:217-22. Links
  • 136
    Fanciulli M, Santulli L, Errichiello L, et al. LGI1 microdeletion in autosomal dominant lateral temporal epilepsy. Neurology. 2012;78:1299-303. Links
  • 137
    Fertig E, Lincoln A, Martinuzzi A, Mattson RH, Hisama FM. Novel LGI1 mutation in a family with autosomal dominant partial epilepsy with auditory features. Neurology. 2003;60:1687-90. Links
  • 138
    Kalachikov S, Evgrafov O, Ross B, et al. Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features. Nat Genet. 2002;30:335-41. Links
  • 139
    Morante-Redolat JM, Gorostidi-Pagola A, Piquer-Sirerol S, et al. Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy. Hum Mol Genet. 2002;11:1119-28. Links
  • 140
    Nobile C, Michelucci R, Andreazza S, et al. LGI1 mutations in autosomal dominant and sporadic lateral temporal epilepsy. Hum Mutat. 2009;30:530-6. Links
  • 141
    Sirerol-Piquer MS, Ayerdi-Izquierdo A, Morante-Redolat JM, et al. The epilepsy gene LGI1 encodes a secreted glycoprotein that binds to the cell surface. Hum Mol Genet. 2006;15:3436-45. Links
  • 142
    Striano P, de Falco A, Diani E, et al. A novel loss-of-function LGI1 mutation linked to autosomal dominant lateral temporal epilepsy. Arch Neurol. 2008;65:939-42. Links
  • 143
    Depienne C, Bouteiller D, Keren B, et al. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles dravet syndrome but mainly affects females. PLoS Genet. 2009;5:e1000381. Links
  • 144
    Dibbens LM, Tarpey PS, Hynes K, et al. X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Nat Genet. 2008;40:776-81. Links
  • 145
    Hynes K, Tarpey P, Dibbens LM, et al. Epilepsy and mental retardation limited to females with PCDH19 mutations can present de novo or in single generation families. J Med Genet. 2010;47:211-6. Links
  • 146
    Kurian MA, Meyer E, Vassallo G, et al. Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy. Brain. 2010;133:2964-70. Links
  • 147
    Poduri A, Chopra SS, Neilan EG, et al. Homozygous PLCB1 deletion associated with malignant migrating partial seizures in infancy. Epilepsia. 2012;53:e146-50. Links
  • 148
    Shen J, Gilmore EC, Marshall CA, et al. Mutations in PNKP cause microcephaly, seizures and defects in DNA repair. Nat Genet. 2010;42:245-9. Links
  • 149
    Chen WJ, Lin Y, Xiong ZQ, et al. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet. 2011;43:1252-5. Links
  • 150
    Heron SE, Grinton BE, Kivity S, et al. PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome. Am J Hum Genet. 2012;90:152-60. Links
  • 151
    Lee HY, Huang Y, Bruneau N, et al. Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. Cell Rep. 2012;1:2-12. Links
  • 152
    Méneret A, Grabli D, Depienne C, et al. PRRT2 mutations:a major cause of paroxysmal kinesigenic dyskinesia in the European population. Neurology. 2012;79:170-4. Links
  • 153
    Ono S, Yoshiura K, Kinoshita A, et al. Mutations in PRRT2 responsible for paroxysmal kinesigenic dyskinesias also cause benign familial infantile convulsions. J Hum Genet. 2012;57:338-41. Links
  • 154
    Pelzer N, de Vries B, Kamphorst JT, et al. PRRT2 and hemiplegic migraine:a complex association. Neurology. 2014;83:288-90. Links
  • 155
    Schubert J, Paravidino R, Becker F, et al. PRRT2 mutations are the major cause of benign familial infantile seizures. Hum Mutat. 2012;33:1439-43. Links
  • 156
    Striano P, Lispi ML, Gennaro E, et al. Linkage analysis and disease models in benign familial infantile seizures:a study of 16 families. Epilepsia. 2006;47:1029-34. Links
  • 157
    Wang JL, Cao L, Li XH, Hu ZM, Li JD, Zhang JG, et al. Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias. Brain. 2011;134:3493-501. Links
  • 158
    Weber YG, Berger A, Bebek N, et al. Benign familial infantile convulsions:linkage to chromosome 16p12-q12 in 14 families. Epilepsia. 2004;45:601-9. Links
  • 159
    Abou-Khalil B, Ge Q, Desai R, et al. Partial and generalized epilepsy with febrile seizures plus and a novel SCN1A mutation. Neurology. 2001;57:2265-72. Links
  • 160
    Baulac S, Gourfinkel-An I, Picard F, et al. A second locus for familial generalized epilepsy with febrile seizures plus maps to chromosome 2q21-q33. Am J Hum Genet. 1999;65:1078-85. Links
  • 161
    Buoni S, Orrico A, Galli L, et al. SCN1A (2528delG) novel truncating mutation with benign outcome of severe myoclonic epilepsy of infancy. Neurology. 2006;66:606-7. Links
  • 162
    Rojo DC, Hamiwka L, McMahon JM, et al. De novo SCN1A mutations in migrating partial seizures of infancy. Neurology. 2011;77:380-3. Links
  • 163
    Claes L, Del-Favero J, Ceulemans B, et al. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet. 2001;68:1327-32. Links
  • 164
    Dichgans M, Freilinger T, Eckstein G, et al. Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet. 2005;366:371-7. Links
  • 165
    Escayg A, MacDonald BT, Meisler MH, et al. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nat Genet. 2000;24:343-5. Links
  • 166
    Freilich ER, Jones JM, Gaillard WD, et al. Novel SCN1A mutation in a proband with malignant migrating partial seizures of infancy. Arch Neurol. 2011;68:665-71. Links
  • 167
    Mantegazza M, Gambardella A, Rusconi R, et al. Identification of an nav1.1 sodium channel (SCN1A) loss-of-function mutation associated with familial simple febrile seizures. Proc Natl Acad Sci U S A. 2005;102:18177-82. Links
  • 168
    McArdle EJ, Kunic JD, George AL Jr. Novel SCN1A frameshift mutation with absence of truncated nav1.1 protein in severe myoclonic epilepsy of infancy. Am J Med Genet A. 2008;146A:2421-3. Links
  • 169
    Moulard B, Buresi C, Malafosse A. Study of the voltage-gated sodium channel beta 1 subunit gene (SCN1B) in the benign familial infantile convulsions syndrome (BFIC). Hum Mutat. 2000;16:139-42. Links
  • 170
    Mulley JC, Scheffer IE, Petrou S, et al. SCN1A mutations and epilepsy. Hum Mutat. 2005;25:535-42. Links
  • 171
    Ohmori I, Ouchida M, Ohtsuka Y, Oka E, Shimizu K. Significant correlation of the SCN1A mutations and severe myoclonic epilepsy in infancy. Biochem Biophys Res Commun. 2002;295:17-23. Links
  • 172
    Orrico A, Galli L, Grosso S, et al. Mutational analysis of the SCN1A, SCN1B and GABRG2 genes in 150 italian patients with idiopathic childhood epilepsies. Clin Genet. 2009;75:579-81. Links
  • 173
    Petrovski S, Scheffer IE, Sisodiya SM, et al. Lack of replication of association between scn1a SNP and febrile seizures. Neurology. 2009;73:1928-30. Links
  • 174
    Schlachter K, Gruber-Sedlmayr U, Stogmann E, et al. A splice site variant in the sodium channel gene SCN1A confers risk of febrile seizures. Neurology. 2009;72:974-8. Links
  • 175
    Vahedi K, Depienne C, Le Fort D, et al. Elicited repetitive daily blindness:a new phenotype associated with hemiplegic migraine and SCN1A mutations. Neurology. 2009;72:1178-83. Links
  • 176
    Zucca C, Redaelli F, Epifanio R, et al. Cryptogenic epileptic syndromes related to SCN1A:twelve novel mutations identified. Arch Neurol. 2008;65:489-94. Links
  • 177
    Berkovic SF, Heron SE, Giordano L, et al. Benign familial neonatal-infantile seizures:characterization of a new sodium channelopathy. Ann Neurol. 2004;55:550-7. Links
  • 178
    Heron SE, Crossland KM, Andermann E, et al. Sodium-channel defects in benign familial neonatal-infantile seizures. Lancet. 2002;360:851-2. Links
  • 179
    Kamiya K, Kaneda M, Sugawara T, et al. A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline. J Neurosci. 2004;24:2690-8. Links
  • 180
    Liao Y, Anttonen AK, Liukkonen E, et al. SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain. Neurology. 2010;75:1454-8. Links
  • 181
    Malacarne M, Gennaro E, Madia F, et al. Benign familial infantile convulsions:mapping of a novel locus on chromosome 2q24 and evidence for genetic heterogeneity. Am J Hum Genet. 2001;68:1521-6. Links
  • 182
    Ogiwara I, Ito K, Sawaishi Y, et al. De novo mutations of voltage-gated sodium channel alphaII gene SCN2A in intractable epilepsies. Neurology. 2009;73:1046-53. Links
  • 183
    Sugawara T, Tsurubuchi Y, Agarwala KL, et al. A missense mutation of the na+channel alpha II subunit gene na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction. Proc Natl Acad Sci U S A. 2001;98:6384-9. Links
  • 184
    Blanchard MG, Willemsen MH, Walker JB, et al. De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy. J Med Genet. 2015;52:330-7. Links
  • 185
    de Kovel CG, Meisler MH, Brilstra EH, et al. Characterization of a de novo SCN8A mutation in a patient with epileptic encephalopathy. Epilepsy Res. 2014;108:1511-8. Links
  • 186
    Veeramah KR, O'Brien JE, Meisler MH, et al. De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Am J Hum Genet. 2012;90:502-10. Links
  • 187
    Arsov T, Mullen SA, Rogers S, et al. Glucose transporter 1 deficiency in the idiopathic generalized epilepsies. Ann Neurol. 2012;72:807-15. Links
  • 188
    Striano P, Weber YG, Toliat MR, et al. GLUT1 muations are a rare cause of familial idiopathic generalized epilepsy. Neurology. 2012;78:557-62. Links
  • 189
    Suls A, Mullen SA, Weber YG, et al. Early-onset absence epilepsy caused by mutations in the glucose transporter GLUT1. Ann Neurol. 2009;66:415-9. Links
  • 190
    Molinari F, Raas-Rothschild A, Rio M, et al. Impaired mitochondrial glutamate transport in autosomal recessive neonatal myoclonic epilepsy. Am J Hum Genet. 2005;76:334-9. Links
  • 191
    Poduri A, Heinzen EL, Chitsazzadeh V, et al. SLC25A22 is a novel gene for migrating partial seizures in infancy. Ann Neurol. 2013;74:873-82. Links
  • 192
    Hamdan FF, Saitsu H, Nishiyama K, et al. Identification of a novel in-frame de novo mutation in SPTAN1 in intellectual disability and pontocerebellar atrophy. Eur J Hum Genet. 2012;20:796-800. Links
  • 193
    Nonoda Y, Saito Y, Nagai S, et al. Progressive diffuse brain atrophy in west syndrome with marked hypomyelination due to SPTAN1 gene mutation. Brain Dev. 2013;35:280-3. Links
  • 194
    Saitsu H, Tohyama J, Kumada T, et al. Dominant-negative mutations in alpha-II spectrin cause west syndrome with severe cerebral hypomyelination, spastic quadriplegia, and developmental delay. Am J Hum Genet. 2010;86:881-91. Links
  • 195
    Hamdan FF, Piton A, Gauthier J, et al. De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy. Ann Neurol. 2009;65:748-53. Links
  • 196
    Saitsu H, Kato M, Mizuguchi T, et al. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nat Genet. 2008;40:782-8. Links
  • 197
    Edvardson S, Baumann AM, Mühlenhoff M, et al. West syndrome caused by ST3Gal-III deficiency. Epilepsia. 2013;54:e24-7. Links
  • 198
    Berryer MH, Hamdan FF, Klitten LL, et al. Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. Hum Mutat. 2013;34:385-94. Links
  • 199
    Mignot C, von Stülpnagel C, Nava C, et al. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. J Med Genet. 2016;53:511-22. Links
  • 200
    Basel-Vanagaite L, Hershkovitz T, Heyman E, et al. Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum. Am J Hum Genet. 2013;93:524-9. Links
  • 201
    Corbett MA, Bahlo M, Jolly L, et al. A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24. Am J Hum Genet. 2010;87:371-5. Links
  • 202
    Duru N, Iseri SA, Selçuk N, Tolun A. Early-onset progressive myoclonic epilepsy with dystonia mapping to 16pter-p13.3. J Neurogenet. 2010;24:207-15. Links
  • 203
    Falace A, Filipello F, La Padula V, et al. TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy. Am J Hum Genet. 2010;87:365-70. Links
  • 204
    Guven A, Tolun A. TBC1D24 truncating mutation resulting in severe neurodegeneration. J Med Genet. 2013;50:199-202. Links
  • 205
    Milh M, Falace A, Villeneuve N, et al. Novel compound heterozygous mutations in TBC1D24 cause familial malignant migrating partial seizures of infancy. Hum Mutat. 2013;34:869-72. Links
  • 206
    Zara F, Gennaro E, Stabile M, et al. Mapping of a locus for a familial autosomal recessive idiopathic myoclonic epilepsy of infancy to chromosome 16p13. Am J Hum Genet. 2000;66:1552-7. Links

Supplementary material

Supplementary Table 1
Epilepsy related genes
Gen Proteina Localización Tipo Alteración Fenotipo Técnica Fuentes
ALG13 Asparagine-linked glycosylation 13, S. cerevisiae, homolog of glycosyltransferase 28 domain-containing 1 Xq23 SNP - LYS94GLU - ASN107SER EETI, EI WES De Ligt et al., 20121 Dimassi et al., 20162 Allen et al., 20133 Michaud et al., 20144 Møller, 20155 Timal et al., 20126
ARHGEF9 Rho guanine nucleotide exchange factor 9 (Collybistin) Xq11 SNP - GLY55ALA - GLN2TER EIEE Array CGH Harvey et al., 20047 Lesca et al., 20118 Lesca et al., 20159 Shimojima et al., 201110
ARX Aristaless-related homeobox, X-Linked Xp21.3 Dup Del SNP - 24-BP DUP, NT428 - PRO353LEU - 1,517-BP DEL - 33-BP DUP - 1-BP DEL, 1465G - 27-BP DUP, NT430 - TYR27TER (c. 81C-G/p.Y27X) - LEU535GLN (c. 1604T > A) EEIT CGH WES mRNA (ratas, Poeta et al.) HPM Bruyere et al., 199911 Claes et al., 199712 Feinberg and Leahy, 197713 Fullston et al., 201014 Giordano et al., 201015 Kato et al., 200416 Kato et al., 200717 Lesca, 20159 Poeta et al., 201318 Proud et al., 199219 Strømme et al., 200220 Strømme et al., 199921 Turner et al., 200222
CACNA1A Subunidad alpha-1-a de canal P/Q de calcio dependiente de voltaje 19p13.13 SNP - ARG1820TER Aus, EGI WES DES Chan et al., 200823 Chioza et al., 200124 Holtmann et al., 200225 Jouvenceau et al., 200126 Kors et al., 200427
CACNA1H Calcium channel, voltage-dependent, T type, alpha 1H subunit 16p13.3 SNP - PHE161LEU - GLU282LYS - VAL831MET - GLY773ASP - ARG788CYS - PRO618LEU - ALA876THR Aus, EGI DES SSCA Chen et al., 200328 Heron et al., 200729 Khosravani et al., 200430 Khosravani et al., 200531 Vitko et al., 200532
CACNA2D1 Calcium channel, voltage-dependent. alpha2/delta subunit 1 7q11-q21 Del - 7.5-MB deletion 7q21.11-q21.12 - 2.72-MB del en 7q21.11 ESG GWEF Array CGH Mefford et al., 201133 Vergult et al., 201534
CDKL5 Cyclin-dependent kinase-like 5 Xp22.13 Del SNP - 1-BP DEL, 183T - IVSAS13, G-A, -1 - CYS152PHE - 4-BP DEL, 166GAAA - 2-BP DEL, 2636CT - ARG175SER - GLN834TER - VS6AS, G-T, -1 - ALA40VAL - ILE72THR - THR288ILE - CYS291TYR - 2-BP INS, 903GA - ARG178PRO EEIT, EI, EMT WES GWEF Array CGH Archer et al., 200635 Elia et al., 200836 Bartnik et al., 201137 Elia et al., 200836 Erez et al., 200938 Møller, 20155 Mefford et al., 201133 Kalscheuer et al., 200339 Nectoux et al., 200640 Nemos et al., 200941 Rademacher et al., 201142 Rosas-Vargas et al., 200843 Russo et al., 200944 Saletti et al., 200945 Scala et al., 200546 Tao et al., 200447 Van Esch et al., 200748 Weaving et al., 200449
CHD2 Chromodomain helicase DNA-binding protein 2 15q26.1 Del SNP - 1-BP DEL, 1809G GLU1412GLYFSTER64 - ARG121TER GLY491VALFSTER13 ARG1644LYSFSTER22 - TRP548ARG - TRP1657TER - IVS15AS, A-C, -2 - ARG466TER Síndrome de Dravet, Lennox-Gastaut y Doose. (Fotosensible) EMA, Aus WES, Targeted sequencing Carvill et al., 2013,50 Chenier et al., 201451 Galizia et al., 201552 Liu et al., 201553 Lund et al., 201454 Rauch et al., 201255 Suls et al., 201356 Thomas et al., 201557 Trivisano et al., 201558
CHRNA7 Cholinergic receptor, nicotinic, alpha 7 15q13.3 Del EGG GWAS CGH Dibbens et al., 200959 Helbig et al., 200960 Mefford et al., 201133
CNTNAP2 Contactin-associated protein-like 2 7q35 Del 1-BP DEL, 3709G EF con regresión. Síndrome Epilepsia Focal-Displasia Cortical GWEF array CGH Targeted sequencing Mefford et al., 201133 Peñagarikan et al., 201161 Strauss et al., 200662
CSTB Cystatin-B 21q22.3 Del SNP - IVS1, G-C, -1 - ARG68TER - (CCCCGCCCCGCG) n EXPANSION, - 12-MER EXPANSION, - PROMOTER REGION - GLY4ARG - 2-BP DEL, 2404TC - GLN71PRO Epilepsia mioclónica progresiva (Síndrome de Unverricht-Lundborg) Complete sequencing of the gene Alakurtti et al., 200563 Bespalova et al., 199764 de Haan et al., 200465 Di Giaimo et al., 200266 Lafrenière et al., 199767 Lalioti et al., 199768 Mazarib et al., 200169 Pennacchio et al., 199670 Virtaneva et al., 199771
DEPDC5 Dominio DEP 5 22q12.3 Del SNP - TYR7TER - ARG555TER - 3-BP DEL, 488TGT - TRP1369TER - 1-BP DEL, 1122A - ARG239TER - ARG328TER - ARG1087TER - ARG487TER - ARG843TER - THR864MET - GLN140TER EFFFM, ELFNAD, ELTMF WES, Direct sequencing Baulac et al., 201572 Berkovic et al., 200473 Callenbach et al., 200374 Dibbens et al., 201375 Ishida et al., 201376 Klein et al., 201477 Martin et al., 201478 Picard et al., 200079 Picard et al., 201480 Scheffer et al., 201481 Scheffer et al., 199882 Xiong et al.,199983
DMRT2, DMRT3 Doublesex- and Mab-3-related transcription factor 2 and factor 3 9p24.3 Del EI Array - CGH Epi4K Consortium and Epilepsy Phenome/Genome Project, 201584
DNM1 Dynamin 1 9q34.11 SNP ALA177PRO LYS206ASN GLY359ALA 130982480C-T 130984491A-T EEIT (Lennox-Gastaut), EI WES Møller, 20155 Boumil et al., 201085 Deciphering Developmental Disorders Study, 201586 Dhindsa et al., 201587 EuroEPINOMICS-RES Consortium et al., 201488
DOCK7 Dedicator for cytokinesis 7 1p31.3 Del SNP - 1-BP DEL, 2510A - ARG1237TER - SER328TER - GLU2078TER EEIT WES Perrault et al., 201489
GABRA1 Gamma-aminobutyric acid (GABA) A receptor, alpha 1 5q34 SNP Del Ins - ALA322ASP - 1-BP DEL, 975C - GLY251SER - ARG112GLN - LYS306THR - 25-BP INS - ASP219ASN EEIT, EMJ, Aus Array - CGH WES Carvill et al., 201490 Cossette et al., 200291 Ding et al., 201092 Epi4K Consortium and Epilepsy Phenome/Genome Project, 201584 Lachance-Touchette et al., 201193 Maljevik et al., 200694
GABRB3 Gamma-aminobutyric acid A receptor, beta 3 15q11 SNP - PRO11SER - SER15PHE - GLY32ARG EI, TCG, T, atonicas, Aus Array - CGH WES Epi4K Consortium and Epilepsy Phenome/Genome Project, 201584 Tanaka et al., 200895 Urak et al., 200696
GABRG2 Receptor GABA-A, Polipéptido gamma-2 5q34 SNP - LYS289MET - ARG43GLN - GLN351TER - ARG139GLY - ARG323GLN EGI, CF, Aus Candidate gene sequencing Audenaert et al., 200697 Baulac et al., 201198 Chaumont et al., 201399 Chiu et al., 2008100 Frugier et al., 2007101 Harkin et al., 2002102 Kananura et al., 2002103 Kang et al., 2006104 Lachance-Touchette et al., 201193 Sancar and Czajkowski, 2004105 Tan et al., 2007106 Wallace et al., 2001107
GNAO1 Guanine nucleotide-binding protein alpha activating 16q12.2 SNP Del - ILE279ASN - ASP174GLY - 21-BP DEL, NT572 - GLY203ARG EEIT CGH WES Lesca, 20159 Nakamura et al., 2013108
GRIN2A Glutamate receptor, ionotropic, N-methyl D-aspartate 2A 16p13.2 SNP GLN218TER IVS4DS, G-A, +1 ASN615LYS LEU649VAL PRO522ARG MET1THR THR531MET IVS5AS, A-G, -2 ARG518HIS PHE652VAL ARG681TER TYR943TER SEA, EF WES Møller, 20155 Carvill et al., 2013109 Endele et al., 2010110 Lesca et al., 2013111 Lemke et al., 2013112 Scheffer et al., 1995113
HCN1 Hyperpolarization-activated cyclic nucleotide-gated potassium channel 1 5p12 SNP ASP401HIS SER100PHE SER272PRO ARG297THR HIS279TYR EEIT CGH WES Lesca, 20159 Nava et al., 2014114
HDAC4 Histone deacetylase 4 2q37.3 EEIT WES Møller, 20155
HIP1 Huntingtin interacting Protein 1 7q11 EI Array - CGH Epi4K Consortium and Epilepsy Phenome/Genome Project, 201584
KCNQ2 Potassium channel, voltage-gated, KQT-like subfamily, member 2 20q13.3 SNP Ins Del TYR284CYS ALA306THR 5-BP INS 1-BP DEL, 1846T ARG214TRP ARG207TRP LYS526ASN SER247TRP 10-BP DEL/1-BP INS, NT761 1-BP DEL, 2127T ARG207GLN ARG213GLN MET546VAL GLY290ASP ALA265VAL EEIT, ENFB CGH WES Lesca, 20159 Bassi et al., 2005115 Berkovic et al., 1994116 Biervert et al., 1998117 Bievert and Steinlein, 1999118 Borgatti et al., 2004119 Dedek et al., 2003120 del Giudice et al., 2000121 Heron et al., 2007122 Saitsu et al., 2012123 Singh et al., 1998124 Weckhuysen et al., 2012125 Wuttke et al., 2007126 Yang et al., 1998127 Zimprich et al., 2006128
KCNT1 Potassium channel, sodium-activated subfamily T, member 1 9q34.4 SNP ARG428GLN ALA934THR ARG474HIS ILE760MET ARG928CYS TYR796HIS ARG398GLN MET896ILE PHE932ILE GLY288SER ELFNAD, EICFM WES Barcia et al., 2012129 Derry et al., 2008130 Heron et al., 2012131 Ishii et al., 2013132 Møller et al., 20155 Ohba et al.,133 Vanderver et al., 2014134
LGI1 Leucine-rich gene, glioma inactivated 1 10q23.33 SNP Del GLU383ALA 1-BP DEL, 835C IVS3AS, C-A, -3 CYS46ARG 1320C-T PHE318CYS IVS5DS, G-A, +1 LEU232PRO ARG136TRP ILE122LYS 81-KB DEL ELTMF Direct sequencing CNV analysis Chabrol et al., 2007135 Fanciulli et al., 2012136 Fertig et al., 2003137 Kalachikov et al., 2002138 Morante-Redolat et al., 2002139 Nobile et al., 2009140 Sirerol-Piquer et al., 2006141 Striano et al., 2008142
PCDH19 Protocadherin 19 Xq22.1 SNP Ins Dup 1-BP INS, 1091C VAL441GLU GLN85TER SER671TER 1-BP INS, 2030T GLU48TER 5-BP DUP, NT1036 ASN557LYS EEIT en mujeres (Ohtahara, Dravet) Microarrays, Systematic resequencing Depienne et al., 2009143 Dibbens et al., 2008144 Hynes et al., 2010145
PLCB1 Phospholipase C, beta-1 20p12.3 Del 0.5-MB DEL EEIT, CPMMI CGH Genome-wide scan Lesca, 20159 Kurian et al., 2010146 Poduri et al., 2012147
PNKP Polynucleotide kinase 3 phosphatase 19q13.33 SNP Dup Del GLU326LYS 17-BP DUP, NT1250 LEU176PHE 17-BP DEL EEIT, Microcefalia-Crisis y Retraso Mental CGH Genome-wide scan Lesca, 20159 Shen et al., 2010148
PRRT2 Proline-rich transmembrane protein 2 16p11.2 Dup Ins SNP Del 1-BP DUP, 649C 1-BP INS, 629C SER317ASN IVS2DS, G-A, +5 ARG240TER 1-BP INS, 516T GLN163TER GLN188TER 1-BP DEL, 629C 1-BP DEL, 291C GLN250TER 1-BP DEL, 650G CIF, CICA WES Møller, 20155 Chen et al., 2011149 Heron et al., 2012150 Lee et al., 2012151 Meneret et al., 2012152 Ono et al., 2012153 Pelzer et al., 2014154 Schubert et al., 2012155 Striano et al., 2006156 Wang et al., 2011157 Weber et al., 2004158
RYR3 Ryanodine receptor 3 15q13.3 EEIT WES Møller, 20155
SCN1A Sodium voltage-gated channel alpha subunit 1 2q24.3 SNP Del ARG1648HIS THR875MET ASP188VAL VAL1353LEU ILE1656MET TRP1204ARG 2-BP DEL, 657AG ARG222TER LEU986PHE LYS1270THR VAL1428ALA THR1709ILE VAL1611PHE MET145THR IVS5N + 5G-A 1-BP DEL, 2528G DEL EX21-26 6.5-Kb DEL 1-BP DEL, 3608A ALA1669GLU ARG862GLY Síndrome de Dravet, CF familiares, EEIT WES SSCA Multiplex ligation-dependent probe amplification Abou-Khalil et al., 2001159 Baulac et al., 1999160 Buoni et al., 2006161 Carranza Rojo et al., 2011162 Claes et al., 2001163 Depienne et al., 2009143 Dichgans et al., 2005164 Escayg et al., 2000165 Freilich et al., 2011165 Mantegazza et al., 2005167 McArdle et al., 2008168 Moulard et al., 1999169 Mulley et al., 2005170 Ohmori et al., 2002171 Orrico et al., 2009172 Petrovsky et al., 2009173 Schlachter et al., 2009174 Vahedi et al., 2009175 Zucca et al., 2008176
SCN2A Sodium channel, voltage-gated, type II, alpha subunit 2q24.3 ARG188TRP LEU1330PHE LEU1563VAL VAL892ILE ARG223GLN ARG1319GLN LEU1003ILE ARG102TER GLU1211LYS ILE1473MET ALA263VAL MET252VAL EEIT Direct sequencing, WES, Genome-wide analysis. Berkovic et al., 2004177 Heron et al., 2002178 Kamiya et al., 2004179 Liao et al., 2010180 Malacarne et al., 2001181 Ogiwara et al., 2009182 Sugawara et al., 2001183
SCN8A Sodium Channel, voltage-gated, type VIII, alpha subunit 12q13.13 SNP ASN1768ASP LEU1290VAL ARG1617GLN ASN1466LYS ASN1466THR ARG223GLY ASN984LYS GLY1451SER EEIT SUDEP WES Targeted capture sequencing Blanchard et al., 2015184 Carvill et al., 201350 De Kobel et al., 2014185 Ohba et al., 2014133 Veeramah et al., 2012186
SLC2A1 Solute carrier family 2 (facilitated glucose transporter), member 1 1p34.2 SNP ARG232CYS ARG223PRO ARG458TRP ASN411SER EGI Direct sequencing, PCR sequencing Arsov et al., 2012187 Striano et al., 2012188 Suls et al., 2009189
SLC25A22 Solute carrier family 25 (mitochondrial carrier, glutamate) member 22 11p15.5 SNP PRO206LEU GLY236TRP GLY110ARG EEIT CGH WES Lesca, 20159 Molinari et al., 2005190 Poduri et al., 2013191
SLC26A1 Solute carrier family 26, (anion exchanger), member 1 4p16 SEA GWEF array CGH Mefford et al., 201130
SLC35A2 Solute carrier family 35 (UDP-galactose transporter) member 2 Xp11.23 Del SNP 2-BP DEL, 433TA 1-BP DEL, 972T SER213PHE EEIT CGH WES Lesca, 20159 Nakamura et al., 2013108
SPTAN1 Alpha, non-erythrocytic, spectrin 1 9q34.11 Del Dup 3-BP DEL, 6619GAG 6-BP DUP, NT6923 3-BP DEL, NT6605 9-BP DUP, NT6908 EEIT CGH Direct sequencing. Lesca, 20159 Hamdan et al., 2012192 Nonoda et al., 2013193 Saitsu et al., 2010194
STXBP1 Syntaxin-binding protein 1 9q34.11 SNP GLY544ASP CYS180TYR MET443ARG VAL84ASP ARG388TER IVS3DS, G-A, +1 GLU283LYS EIEE WES Møller, 20155 Carvill et al., 2014195 Hamdan et al., 2009190 Saitsu et al., 2008196
STX1B Syntaxin 1B 16p11.2 Síndromes asociados con epilepsia febril WES Møller, 20155
ST3GAL3 ST3 beta-galactoside alpha-2,3-sialyltransferase 3 1p34.1 SNP ALA320PRO EEIT CGH WES Lesca, 20159 Edvarson et al., 2013197
SYNGAP1 Synaptic RAS-GTPase-activating protein 1 6p21.32 SNP PRO562LEU TRP267TER ARG143TER c. 321_324del c. 427C > T/p.Arg143 EEIT, mioclónicas, Aus WES Barryer et al., 2013198 Carvill et al., 2013199 Mignot et al., 201650
SZT2 Seizure threshold 2, mouse homolog 1p34.2 SNP ARG25TER GLN698TER c. 1496G-T - EEIT CGH WES Basel-Vanagaite et al., 2013200 Lesca, 20159
TAS2R1, FAM173B, CCT5, MTRR Taste receptor, type 2, member 1/family with sequence similarity 173, member B/chemokine receptor 5/5- methyltetrahydrofolate-homocysteine methyltransferase reductase 5p15 FS, focal, TCG, aA, SE Array - CGH Epi4K Consortium and Epilepsy Phenome/Genome Project, 201584
TBC1D24 TBC1 domain family, member 24 16p13.3 SNP Del ASP147HIS ALA509VAL PHE251LEU 2-BP DEL, 969GT PHE229SER CYS156TER EEIT, EMIF CGH Candidate gene sequencing Lesca, 20159 Corbett et al., 2010201 Duru et al., 2010202 Falace et al., 2010203 Guven and Tolun, 2013204 Milh et al., 2013205 Zara et al., 2000206
UBE3A Ubiquitin protein ligase E3A 15q11 Del EMA GWEF array CGH Mefford et al., 201133
GWAS: Genome Wide Association Study; WES: Whole Exome Sequencing; Array-CGH: Array Comparative Genome Hybridization; NGS: Next Generation Sequencing; HPM: Highly Polymorphic Microsatellite; DES: Direct Exon Sequencing; SSCA: Single-Stranded Conformation Analysis; EF: Epilepsia Focal; TCG: Crisis Tónico Clónicas Generalizadas; T: Crisi Tónicas; CF: Crisis Febriles; aA: Ausencias Atípicas; SE: Status Epiléptico; Aus: Ausencias; EMA: Epilepsia Mioclónica-Atónica; SEA: Síndrome Epilepsia-Afasia; ESG: Epilepsia Sintomática Generalizada; EMJ: Epilepsia Mioclónica Juvenil; EEIT: Encefalopatía Epiléptica Infantil Temprana; EGG: Epilepsia Generalizada Genética; EI: Espasmos Infantiles;; EGI: Epilepsia Generalizada Idiopática; CICA: Convulsiones Infantiles y Coreo-Atetosis; EICFM: Epilepsia Infantil con Crisis Focales Migratorias; CPMMI: Crisis Parciales Malignas Migratorias de la Infancia; EMT: Epilepsia Mioclónica Tardía; EFFFM: Epilepsia Focal Familiar de Focos Múltiples; ELFNAD: Epilepsia del Lóbulo Frontal Nocturna Autosómica Dominante; ELTMF: Epilepsia del Lóbulo Temporal Mesial Familiar; ENFB: Epilepsia Neonatal Familiar Benigna; CIF: Crisis Infantiles Familares; SUDEP: Suden Unexpected Death of someone with Epilepsy; EMIF: Epilepsia Mioclónica Infantil Familiar
Genomic studies in epilepsy
  • Rev. med. Hosp. Gen. Méx.  vol. 82n. 1Genomic studies in epilepsy Guzmán-Jiménez Diana E. 1 2 Flores-Ramírez Erika L. 2 3 Velasco-Monroy Ana L. 2 * Author affiliationPermissions
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