Epilepsy genes

By Li Dali, Ph.D.

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If seizures are caused by a known or presumed genetic defect or issue related to epilepsy, it is believed that epilepsy has a genetic origin. It is possible for genetic epilepsy to not be hereditary. In some cases, a child may develop certain genetic pathogenic variants (or gene alterations) without inheriting them from either parent. Additionally, certain epilepsies with a genetic basis may also have other environmental factors contributing to their development.

After scouring multiple databases (OMIM, HGMD, and EpilepsyGene) and recent publications on PubMed, we identified 977 genes linked to epilepsy. These genes were sorted into four categories based on the manifestation of epilepsy in phenotypes. Among them, 84 genes were classified as epilepsy genes, causing epilepsies or syndromes with epilepsy as the primary symptom. Additionally, 73 genes were categorized as neurodevelopment-associated genes, linked to both brain-development malformations and epilepsy. Another 536 genes were considered epilepsy-related, associated with physical or systemic abnormalities and epilepsy or seizures. Finally, we discovered 284 genes that may be associated with epilepsy, but further verification is necessary.

Genes associated with epilepsy and neurodevelopment:

Holoprosencephaly PTCH1a

Band-like calcification with simplified gyration and polymicrogyria OCLN

Bilateral frontoparietal polymicrogyria GPR56

Bilateral perisylvian polymicrogyria GPR56

Bilateral temporooccipital polymicrogyria FIG4a

CK syndrome NSDHL

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome PIK3R2a

Polymicrogyria with optic nerve hypoplasia TUBA8

Rolandic epilepsy, speech dyspraxia, and mental retardation SRPX2

Symmetric or asymmetric polymicrogyria TUBB2Ba

Periventricular heterotopia FLNA

Periventricular heterotopia with microcephaly ARFGEF2

Periventricular nodular heterotopia ERMARDa

Subcortical laminar heterotopia DCX, PAFAH1B1a

Tuberous sclerosis TSC1, TSC2

Complex cortical dysplasia with other brain malformations KIF2A, KIF5C, TUBB2A, TUBB3a, TUBG1a

Cortical dysplasia-focal epilepsy syndrome CNTNAP2

Occipital cortical malformations LAMC3

Pontocerebellar hypoplasia AMPD2, CLP1, EXOSC3a, PCLOa, SEPSECS, TSEN2a, TSEN54, VPS53, TSEN15

Mental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearance OPHN1a

Dentatorubro-pallidoluysian atrophy ATN1

Idiopathic basal ganglia calcification SLC20A2a, XPR1a

White matter and others

Agenesis of the corpus callosum with peripheral neuropathy SLC12A6

Leukodystrophy and acquired microcephaly with or without dystonia PLEKHG2a

Nonsyndromic hydrocephalus CCDC88C, MPDZa

Porencephaly COL4A2a

Schizencephaly EMX2

General brain malformation

Lissencephaly TUBA1A, LAMB1, RELN, ARX, DCX, PAFAH1B1a

Lissencephaly with cerebellar hypoplasia CDK5a

Lissencephaly with microcephaly KATNB1, NDE1

Epilepsy, hearing loss, and mental retardation syndrome SPATA5

Galloway-Mowat syndrome WDR73a

Mental retardation and microcephaly with pontine and cerebellar hypoplasia CASK

Microcephaly-capillary malformation syndrome STAMBP

Microcephaly, epilepsy, and diabetes syndrome IER3IP1

Microcephaly, seizures, and developmental delay PNKP

Microcephaly, short stature, and impaired glucose metabolism PPP1R15Ba, TRMT10A

Microcephaly, short stature, and polymicrogyria with seizures RTTN

Microcephaly with or without chorioretino-pathy, lymphedema, or mental retardation KIF11

Postnatal progressive microcephaly, seizures, and brain atrophy MED17

Primary microcephaly ANKLE2a, ASPM, CENPEa, CENPJa, MFSD2A, SASS6a

Primary microcephaly with or without cortical malformations WDR62a

Progressive microcephaly with seizures and cerebral and cerebellar atrophy QARS

Seizures, cortical blindness, microcephaly syndrome DIAPH1

Macrocephaly, dysmorphic facies, and psychomotor retardation HERC1a

Polyhydramnios, megalencephaly, and symptomatic epilepsy STRADA

X-linked epilepsy with variable learning disabilities and behavior disorders SYN1

Psychomotor retardation, epilepsy, and craniofacial dysmorphism SNIP1

Epilepsy-related genes:

Cavernous malform-ations CCM1, KRIT1

Long QT syndrome CALM2, KCNQ1, KCNJ5, CAV3

Moyamoya disease GUCY1A3, RNF213

Others (cerebral amyl-oid angiopathy, etc.) COL4A1, PRNP, PROS1, CTC1, F2, JAM3

Alzheimer disease APP, PSEN1, PSEN2

Angelman syndrome UBE3A (IC)

Autism CHD8, TMLHE, RPL10, SLC9A9

Fragile X syndrome FMR1

Frontotemporal dementia MAPT

Mental retardation ARID1A, ARID1B, ASXL1, AUTS2, BRAF, DEAF1, DYNC1H1, GNB1, HIVEP2, KAT6A, KIAA0442, KIF1A, MBD5, MED13L, MYT1L, NONO, PPP2R1A, PPP2R5D, PURA, SETBP1, SMARCA2, SMARCA4, SMARCB1, SMARCE1, SYNGAP1, TCF4, ZEB2, ANK3, ERCC6, FMN2, FTO, GRIK2, HERC2, KPTN, LMAN2L, MAN1B1, MED25, METTL23, NRXN1, PGAP1, PIGG, PUS3, SOBP, TRAPPC9, IQSEC2, SLC9A6, SYP, USP9X, ZDHHC15, AP1S2, ATP6AP2, CLIC2, CUL4B, DLG3, FGD1, GRIA3, HCFC1, IL1RAPL1, KDM5C, KIF4A, MECP2, MID2, PAK3, PHF6, RAB39B, SMS, TAF1, THOC2, UBE2A, CACNG2, COL4A3BP, DYRK1A, FTSJ1, GATAD2B, GDI1, GPT2, GRIN1, MEF2C (IC), SHROOM4

Others (McLeod syndrome, progressive encephalopathy, etc.) RAI1 (IC), SERPINI1, BSCL2, XK, MTOR

Congenital disorder of glycosylation ALG1, ALG11, ALG2, ALG3, ALG6, CAD, COG4, COG6, DOLK, DPAGT1, DPM1, DPM2, MOGS, MPDU1, NGLY1, RFT1, SLC39A8, STT3A, STT3B, SLC35A2, SSR4, ALG12, ALG9, COG7, COG8

Joubert syndrome AHI1, CC2D2A, CSPP1, OFD1

Microphthalmia BMP4, OTX2, RBP4, SOX2, NAA10

Multiple congenital anomalies-hypotonia-seizures syndrome PIGN, PIGT, PIGA

Muscular dystrophy CHKB, LAMA2, TRAPPC11

Muscular dystrophy-dystroglycanopathy B3GNT1, B4GAT1, FKTN, GMPPB, POMGNT1, POMK, POMT1, POMT2

Neurofibromatosis NF1

Neuropathy DNMT1, SPTLC2, ABHD12

Rett syndrome FOXG1 (IC)

Spinal muscular atrophy with progressive myo-clonic epilepsy ASAH1

Sturge–Weber syndrome GNAQ

Zellweger syndrome PEX2, PEX13, PEX14, PEX19, PEX3

Others (craniosynost-osis, thanatophoric dysplasia, etc.) ACTB, ACTG1, ACVR1, ADNP, DNMT3A, EFTUD2, EHMT1 (IC), FAM111A, FGFR2, FGFR3, GATA6, HNF1B, KCNH1, KCNJ6, KMT2A, MAF, MAGEL2, MAPRE2, MARCA2, MSX2, NOTCH1, NSD1, POGZ, PTEN, PUF60, SATB2, SETD2, SOX5, ZSWIM6, AGPS, ALDH18A1 (IC), AP3D1, ARNT2, ATP6V0A2, BRAT1, C12orf57, C19orf61, CCDC88A, CEP164, CLPP, COL18A1, CRB2, CRLF1, DHCR24, DOCK6, EPG5, EXT2, FAT4, GNPAT, GPSM2, GPX4, LRP2, MKS1, NANS, NIN, PARN, PEX5, PIGL, RAB18, RAPSN, ROGDI, SLC33A1, SLC35A3, TELO2, XPNPEP3, AMER1, DXS423E, NDUFB11, NHS, SMC1A

Herpes simplex ence-phalitis IRF3, TICAM1, TRAF3

Immunodeficiency BCL10, CORO1A, IFNAR2, ISG15, ORAI1, PGM3, PRKDC, STAT1, STAT2, ATP6AP1

Inflammatory disorder IFIH1, NOD2, CD59, PSMB8

Others (candidiasis, neutropenia, etc.) RANBP2, CARD9, DOCK8, FADD, HAX1, CPT2

Aciduria ACADSB, AUH, C2orf25, CLPB, CTH, D2HGDH, DHTKD1, DPYS, GLYCTK, MMAA, MMADHC, MTR, SLC25A1, ACSF3, IDH2

Amino acid metabolic disturbance AASS, ALDH4A1, AMT, ARG1, GCH1, GLDC, GLUL, LIAS, PRODH, QDPR, SLC25A15

Coenzyme Q10 deficiency COQ2, COQ4, COQ6, COQ8A, COQ9, PDSS2

Combined oxidative phosphorylation deficiency CARS2, EARS2, FARS2, GFM1, GTPBP3, MRPS22, MTFMT, MTO1, NARS2, RMND1, TXN2, VARS2, AIFM1

Diabetes mellitus ABCC8, KCNJ11, ZFP57

Enzymatic deficiency ATP1A2, RYR1, ABAT, ACADS, ACOX1, ACY1, ADK, ADSL, AMACR, ASNS, ATIC, BCKDHA, CPS1, DHFR, DLD, DPYD, FAR1, HIBCH, MCCC1, MCCC2, MLYCD, MTHFR, NADK2, OPLAH, PC, PDHX, PDX1, PHGDH, PSAP, PSAT1, PSPH, SCO2, SLC25A20, UPB1, HSD17B10, PDHA1, GK, MAOA, NDP, OTC, PGK1, BCKDK, HADHA, HMGCS2, NAT8L, PEX7, POMC

Folate malabsorption SLC46A1

Folate transport deficiency FOLR1

Glycogen storage disease AGL, GYS1

Hormone metabolism dysfunction CACNA1D, GLI2, PROK2, THRB, MCM8, MRAP, HESX1, AVPR2, ANOS1, FGF8

Hyperphosphatasia with mental retardation syndrome PGAP2, PGAP3, PIGO, PIGV, PIGW, PIGY

Hypocalcemia GNA11

Hypoglycemia AKT2, GCK, INSR

Hypomagnesemia TRPM6, CNNM2, EGF

Hypoparathyroidism PTH

Leigh syndrome LRPPRC, NDUFA2, NDUFAF6, NDUFS4, NDUFS8

Lipid storage disorder NPC1, NPC2

Menkes disease ATP7A

Mitochondrial disease (progressive external ophthalmoplegia with mitochondrial DNA deletions, etc.) POLG2, ATP5A1, ATPAF2, BCS1L, BOLA3, BRP44L, C10orf2, FBXL4, MPC1, PNPLA8, POLG, RRM2B, RTN4IP1, SDHD, SUCLA2, TMEM70, UQCC2, APOPT1, COX10, COX6B1, COX8A, FASTKD2, PET100, FOXRED1, NDUFA1, NDUFAF3, NDUFV1, NUBPL

Mucopolysaccharidosis HGSNAT, IDS

Neuronal ceroid lipofuscinosis DNAJC5, CLN3, CLN5, CLN6, CLN8, CTSD, CTSF, GRN, MFSD8, PPT1, TPP1

Thiamine metabolism dysfunction syndrome SLC19A3, TPK1

Vitamin D-dependent rickets CYP27B1

Others (brain iron accumulation, Salla disease, etc.) ANKH, COL3A1, DNM1L, TTR, ARHGDIA, CYB5R3, ECM1, ETFDH, ETHE1, GAMT, GBA, HADHB, HEXA, HSD17B4, KCNJ10, LARS2, MOCS2, PIGM, PLA2G6, SLC17A5, TANGO2, FTL, SLC16A1, WDR45, SLC6A8, GPHN

Cerebellar ataxia CAMTA1, SLC9A1

Dyskinesia PDE10A

Dystonia SGCE, ACO2, CRYAB, NALCN, TBCK, UNC80, GLRA1, SPR

Episodic ataxia KCNA1, SLC1A3

Episodic hemiplegia ATP1A3

Huntington disease HTT

Parkinson disease LRRK2, DNAJC6, SYNJ1

Spastic ataxia AFG3L2, SACS

Spastic paraplegia NIPA1, AP4B1, AP4E1, AP4S1, ERLIN2, GJC2, HACE1, TECPR2, ZFYVE26, PLP1

Spastic quadriplegia ADD3, ELOVL4, GAD1, SLC1A4

Spinocerebellar ataxia ATXN10, ITPR1, TBP, ANO10, GRM1, RUBCN, SNX14, SYT14, TDP2, TDP1

Alexander disease GFAP

Krabbe disease GALC

Leukodystrophy TUBB4A, AIMP1, ARSA, HSPD1, POLR3B, VPS11

Leukoencephalopathy CSF1R, DARS2, EIF2B1, HEPACAM, MLC1, RNASET2

Glioblastoma BRCA2

A total of 73 genes have been identified as being associated with neurodevelopment, while 536 genes have been linked to epilepsy. The presence of observable neurodevelopmental abnormalities and physical or systemic irregularities can serve as crucial indicators for diagnosis and offer valuable insights for developing a cost-efficient genetic testing plan tailored to a specific patient population.

Follow the link of the selected polymorphism to read a brief description of how the selected polymorphism affects Epilepsy and see a list of existing studies.

SNP polymorphisms related to the topic Epilepsy:

About The Author

Li Dali, a National Foundation for Outstanding Youth Fund recipient, is a researcher at the School of Life Sciences in East China Normal University. He earned his PhD in genetics from Hunan Normal University in 2007 and conducted collaborative research at Texas A&M University during his doctoral studies. Li Dali and his team have optimized and innovated gene editing technology, leading to the establishment of a world-class system for constructing gene editing disease models.

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