Genetic and epigenetic mechanisms of epilepsy: a review

Figures & data

Table 1 Major linkage loci reported for epilepsies

Location	Epilepsy syndrome	Gene	Reference	PMID
2q24	Benign familial infantile convulsions	SCN3A	^Citation184	11326335
2q24	GEFS+	SCN1A	^Citation15	10521305
2q24	GEFS+	SCN2A	^Citation17	18242854
2q24	GEFS+	SCN9A	^Citation17	18242854
2q34	GGE		^Citation185	22242659
3q26	A benign form of mesial TLE		^Citation12	24315020
5q34	A broad spectrum of familial GGE syndromes		^Citation185	22242659
5q14-q15	Febrile seizures and epilepsy		^Citation186	16273391
6p12	JME		^Citation187	12439895
6p21.3	JME	TAP-1	^Citation188	12830434
6p21.3	JME	BRD2	^Citation20	1901453
6q24	Lafora progressive myoclonus epilepsy	EPM2A	^Citation24	9345091
7p12.1-7q11.22	PME	KCTD7	^Citation27	25060828
7q32	Myoclonic seizures-related photosensitivity		^Citation189	17123300
8q24	IGE	KCNQ3	^Citation192	8528209
8q24	CAE	KCNK9	^Citation32	9758624
10q24	Partial epilepsy		^Citation130	7647791
	ADPEAF		^Citation39	11879388
10q22-24	ADPEAF	LGI1	^Citation128	11978770
10q25-q26	Generalized tonic-clonic seizure		^Citation190	16130088
13q31.3	GGE		^Citation185	22242659
15q14	RE		^Citation191	9855510
16p13	Familial autodominant recessive IME of infancy	TBC1D24	^Citation40	10741954
19q13	GEFS+	SCN1B	^Citation185	22242659
22q11-12	Familial partial epilepsy with variable foci	DEPDC5	^Citation193	20659149
22q13.11	Recessive genetic epilepsy with febrile seizures plus	TBC1D22A	^Citation13	24067191

Abbreviations: GEFS+, generalized epilepsy with febrile seizures plus; GGE, genetic generalized epilepsy; TLE, temporal lobe epilepsy; JME, juvenile myoclonic epilepsy; PME, progressive myoclonic epilepsy; IGE, idiopathic generalized epilepsy; CAE, childhood absence epilepsy; ADPEAF, autosomal dominant partial epilepsy with auditory features; RE, rolandic epilepsy; IME, infantile myoclonic epilepsy.

Table 2 Summary of CNVs identified for epilepsy

Locus	CNVs	Genes	Reference	Accession ID
2p16.3	Exon-disrupting deletions	NRXN1	^Citation12	25243798
2q24.2-q24.3	Duplication/deletion	SCN1A, SCN2A	^Citation194	23016767
6p12.1	Microduplication	BMP5	^Citation57	25923336
7q11.22	Deletion	AUTS2	^Citation48	20502679
7q32.3	Microdeletion	PODXL	^Citation57	25923336
7q35	Deletion, hemizygous deletions	CNTNAP2	^Citation48	20502679
15q11.2	Microdeletion	NIPA2, CYFIP1	^Citation49	19843651
15q13.3	Microdeletion	CHRNA7	^Citation48	20502679
16p13.11	Deletion	NDE1	^Citation51	22523559
16p13.2	Microdeletion	GRIN2A, PRRT2	^Citation61	24372385

Abbreviation: CNV, copy number variant.

Table 3 Whole-exome sequencing found variants associated with epilepsy

Locus	Gene symbol	Product	Phenotype
2q35	INHA	Inhibin, alpha	EGTCA
3p14.1	PRICKLE2	Homolog 2 on chromosome 3	PME
4q21.1	SCARB2	Scavenger receptor class B, member 2	PME
6p21.3	SYNGAP1	Synaptic RasGTPase activating protein 1	EMA
12q12	PRICKLE	Prickle homolog 1 on chromosome 12	PME
13q34	CARS2	Csteinyl-tRNA synthetase 2, mitochondrial (putative)	PME
15q23	CLN6	Ceroid-lipofuscinosis, neuronal 6	TOPME
17q21.34	GOSR2	Golgi SNAP receptor complex member 2	PME
16p11.2	PRRT2	Proline-rich transmembrane protein 2	BFNIS
16p13.3	RBFOX1	RNA-binding protein, fox-1 homolog (C. elegans) 1	IGE/RE
17q25.3	RBFOX3	RNA-binding protein, fox-1 homolog (C. elegans) 3	RE
21q22.3	COL6A2	Collagen type VI alpha 2	PME
22q12	DEPDC5	Dishevelled, Egl-10 and Pleckstrin domain-containing protein 5	ADFE

Abbreviations: EGTCA, epilepsy with generalized tonic-clonic seizures on awakening; PME, progressive myoclonus epilepsy; EMA, epilepsy with myoclonic absences; TOPME, teenage-onset progressive myoclonus epilepsy; C. elegans, Caenorhabditis elegans; IGE, idiopathic generalized epilepsy; RE, rolandic epilepsy; ADFE, autosomal dominant focal epilepsy.

Table 4 Genetic loci identified and recommended for genetic testing in epilepsy by ILAE

Locus	Gene	Product	Phenotype	ILAE
1q21-23	ATP1A2	Sodium-potassium ATPase	RE	*
19p13	CACNA1A	Cav2.1 (calcium channel)	AE	*
8p21	CHRNA2	α2 subunit (nACh receptor)	ADNFLE	*
20q13.2-q13.3	CHRNA4	α4 subunit (nACh receptor)	ADNFLE	*
1q21	CHRNB2	β2 subunit (nACh receptor)	ADNFLE	*
6p12-p11	EFHC1	EF-hand motif protein	JME	*
5q34-q35	GABRA1	α1 subunit (GABAR)	JME	*
5q34	GABRG2	γ2 subunit (GABAR)	GEFS+	*
15q12	GABRB3	GABAR, beta 3	CEA
16p13.2	GRIN2A	Glutamate receptor, ionotropic, NMDA 2A	RE
12p13	KCNA1	Kv1.1 (potassium channel)	FE	*
10q22	KCNMA1	Calcium-activated potassium channels	GE	*
3q26.3-q27	KCNMB3	Potassium large conductance calcium-activated channel, subfamily M beta 3	JAE
1q23.2	KCNJ10	Potassium inwardly rectifying channel, subfamily J, member 10	IGE
20q13.3	KCNQ2	Kv7.2 (potassium channel)	BFNS	*
8q24	KCNQ3	Kv7.3 (potassium channel)	BFNS	*
9q34.3	KCNT1	Potassium channel, subfamily T, member 1	ADNFLE
10q24	LGI1	LRR protein	ADLTE	*
19q13.1	SCN1B	β1 subunit (sodium channel)	GEFS+	*
2q23-q24.3	SCN2A	Nav1.2 (sodium channel)	BFNIS	*
1p35-p31.1	SLC2A1	GLUT1	IGE	*
9q34.1	STXBP1	Syntaxin-binding protein 1	EIEE	*

Note:

* Recommended for genetic testing in epilepsy by ILAE.

Abbreviations: ILAE, International League Against Epilepsy; RE, rolandic epilepsy; AE, absence epilepsy; ADNFLE, autosomal dominant nocturnal frontal lobe epilepsy; JME, juvenile myoclonic epilepsy; GABAR, GABAA receptor; GEFS+, genetic epilepsy with febrile seizures plus; CEA, childhood absence epilepsy; NMDA, N-methyl-d-aspartate; FE, focal epilepsy; GE, generalized epilepsy; JAE, juvenile absence epilepsy; IGE, idiopathic generalized epilepsy; BFNS, benign familial neonatal idiopathic generalized epilepsy; LRR, leucine-rich repeat; ADLTE, autosomal dominant lateral temporal epilepsy; GLUT1, glucose transporter type 1; EIEE, early infantile epileptic encephalopathy with suppression-burst.

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