Genomic studies in epilepsy

Guzmán-Jiménez, Diana E.; Flores-Ramírez, Erika L.; Velasco-Monroy, Ana L.; Guzmán-Jiménez, Diana E.; Flores-Ramírez, Erika L.; Velasco-Monroy, Ana L.

doi:10.24875/hgmx.m19000001

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Revista médica del Hospital General de México

versión On-line ISSN 2524-177Xversión impresa ISSN 0185-1063

Rev. med. Hosp. Gen. Méx. vol.82 no.1 Ciudad de México ene./mar. 2019 Epub 06-Sep-2021

https://doi.org/10.24875/hgmx.m19000001

Review articles

Genomic studies in epilepsy

Diana E. Guzmán-Jiménez¹²

Erika L. Flores-Ramírez²³

Ana L. Velasco-Monroy²^*

^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

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).

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).

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)

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.

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Ethical disclosures

Protection of human and animal subjects. The authors declare that no experiments were performed on humans or animals for this study.

Confidentiality of data. The authors declare that they have followed the protocols of their work center on the publication of patient data.

Right to privacy and informed consent. The authors declare that no patient data appear in this article.

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

Received: July 29, 2016; Accepted: March 15, 2017

^*Correspondence: Ana Luisa Velasco-Monroy E-mail: analuisav@yahoo.com

Sociedad Médica del Hospital General de Mexico. Published by Permanyer. This is an open ccess article under the CC BY-NC-ND license