GENE ABNORMALITIES

Current knowledge regarding the contribution of gene abnormalities to epilepsy derives from specific molecular genetic studies that have been well replicated and even become the basis of diagnostic testing, or from appropriately designed family studies. Some of the important gene abnormalities that cause epilepsy and/or have particular features that are important to recognize are presented in this section of EpilepsyDiagnosis.org.

• AKT3
• ARFGEF2
• ARHGEF9
• ARX
• CACNA1A
• CACNB4
• CDKL5
• CHD2
• CHRNA2
• CHRNA4
• CHRNB2
• CLCN2
• COL4A1
• DCX
• DEPDC5
• EFHC1
• FKRP
• FKTN
• FLNA
• FMR1 (FRAGILE X SYNDROME)
• FOXG1
• GABRA1
• GABRD
• GABRG2
• GLI3
• GNAQ
• GRIN2A
• KCNQ2
• KCNQ3
• KCNT1
• LARGE
• LGI1
• LIS1
• MECP2
• NPRL2
• NPRL3
• PCDH19
• PIK3CA
• PIK3R2
• PLCB1
• PNKP
• POMT1
• POMT2
• PRRT2
• RELN
• SCN1A
• SCN1B
• SCN2A
• SLC2A1
• SLC25A22
• SPTAN1
• STXBP1
• TBC1D24
• TCF4 (PITT HOPKIN SYNDROME)
• TSC1
• TSC2
• TUBA1A
• WDR62
• ZEB2 (MOWAT WILSON SYNDROME)

AKT3

The v-akt murine thymoma viral oncogene homolog 3 gene is located on chromosome 1q44. The protein encoded by this gene is a member of the AKT serine/threonine protein kinase family and is a regulator of cell proliferation and differentiation in response to insulin and growth factors. AKT3 gene abnormalities can cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome.

ARFGEF2

The ADP ribosylation factor guanine nucleotide exchange factor 2 gene is located on chromosome 20q13.13. The protein encoded by this gene is a protein that helps with the movement of vesicles within the cell, this being important in neuronal cell migration in fetal life. ARFGEF2 gene abnormalities can cause periventricular nodular heterotopia, with microcephaly.

ARHGEF9

The Cdc42 guanine nucleotide exchange factor (GEF) 9 (ARHGEF9) gene, located on chromosome Xq11.1, encodes a protein that regulates other genes. Pathogenic variants in ARHGEF6 cause early-infantile developmental and epileptic encephalopathy syndrome with hyperekplexia. Seizures may be provoked by tactile stimulation or extreme emotion.

ARX

The aristaless related homeobox (ARX) gene, located on chromosome Xp21.3, is responsible for the gene product ARX protein, a transcription factor. The ARX protein is important in early embryonic development influencing differentiation and migration of cells in the pancreas, testes, brain and skeletal muscles. Pathogenic variants in ARX are found in Partington syndrome (a neurological disorder associated with intellectual impairment and focal dystonia of the hands), early-infantile developmental and epileptic encephalopathy syndrome, X-linked infantile epileptic spasm syndrome, X-linked generalized epilepsy with myoclonic seizures and intellectual impairment and in X-linked structural brain abnormality such as lissencephaly (which may be accompanied by ambiguous genitalia). ARX pathogenic variants account for nearly 10% of all X-linked intellectual impairment.

CACNA1A

The calcium channel, voltage-dependent, P/Q type, alpha 1A subunit (CACNA1A) gene, located on chromosome 19p13, encodes the alpha-1 subunit of a calcium channel. Pathogenic variants in this gene have been linked to episodic ataxia, familial hemiplegic migraine and spinocerebellar ataxia type 6. Variants in CACNA1A have been linked to susceptibility to genetic generalized epilepsies with absence seizures.

CACNB4

The calcium channel, voltage-dependent, beta 4 subunit (CACNB4) gene, located on chromosome 2q22-q23, encodes the beta-4 subunit of a calcium channel. Variants in this gene have been linked to episodic ataxia and generalized epilepsies including juvenile myoclonic epilepsy.

CDKL5

The cyclin-dependent kinase-like 5 (CDKL5) gene, located on chromosome Xp22, encodes a CDKL5 protein that acts as a kinase (changing activity of other proteins). One of the proteins affected by CDKL5 is MECP2 protein.

• More than 10 pathogenic variants in CDKL5 have been identified in girls with atypical (early onset seizure variant) Rett syndrome. This severe form of the disorder includes many of the features of classic Rett syndrome (including developmental delay, loss of language skills, and repeated hand wringing movements), but also causes recurrent seizures beginning in infancy.
• Pathogenic variants in CDKL5 are also reported in X-linked epileptic spasms with intellectual impairment, seen more commonly in females but also reported in males.
• Pathogenic variants in CDKL5 are also reported in early-infantile developmental and epileptic encephalopathy syndrome

CHD2

The chromodomain helicase DNA binding protein 2 (CHD2) gene, located on chromosome 15q26, is a gene that modifies transcription. CHD2 gene abnormalities have been linked to epilepsy of infancy with migrating focal seizures.

CHRNA2

The cholinergic receptor, nicotinic, alpha 2 (neuronal) (CHRNA2) gene, located on chromosome 8p21, encodes a subunit of the neuronal nicotinic acetylcholine receptor. Pathogenic variants in CHRNA2 are found as a rare cause of sleep-related hypermotor (hyperkinetic) epilepsy.

CHRNA4

The cholinergic receptor, nicotinic, alpha 4 (neuronal) (CHRNA4) gene, located on chromosome 20q13.2-q13.3, encodes a subunit of the neuronal nicotinic acetylcholine receptor. Pathogenic variants in CHRNA2 are found in patients with sleep-related hypermotor (hyperkinetic) epilepsy

CHRNB2

The cholinergic receptor, nicotinic, beta 2 (neuronal) (CHRNB2) gene, located on chromosome 1q21.3, encodes a subunit of the neuronal nicotinic acetylcholine receptor. Pathogenic variants in CHRNB2 are found in patients with sleep-related hypermotor (hyperkinetic) epilepsy.

CLCN2

The chloride channel, voltage-sensitive 2 (CLCN2) gene, located on chromosome 3q27.1, encodes a voltage-gated chloride channel. Variants in CLCN2 have been linked with genetic/idiopathic generalized epilepsies including juvenile absence epilepsy, juvenile myoclonic epilepsy and epilepsy with generalized tonic-clonic seizures alone.

COL4A1

The collagen type IV alpha 1 gene is located on chromosome 13q34. The protein encoded by this gene is a component of type IV collagen, an important component of basement membranes. COL4A1 gene abnormalities can cause familial early life stroke resulting in 'familial porencephaly'. A small number of people with schizencephaly have been found to have COL4A1 pathogenic variants.

DCX

The doublecortin gene is located on chromosome Xq22.3-q23. The protein encoded by this gene is doublecortin, which binds to and is important in maintaining stability of microtubules. Microtubules are the scaffolding that allows for normal cell migration in the developing brain. DCX gene abnormalities can cause either lissencephaly or subcortical band heterotopia.

DEPDC5

The DEP domain containing 5 (DEPDC5) gene, located on chromosome 22q12.3, encodes a protein that may be involved in membrane trafficking and/or G protein signaling. Pathogenic variants in DEPDC5 have been identified in familial epilepsies with focal seizures including familial focal epilepsy with variable foci, familial mesial temporal lobe epilepsy and sleep-related hypermotor (hyperkinetic) epilepsy. Pathogenic variants in DEPDC5 have also been found in patients with focal cortical dysplasia, including in familial cases.

EFHC1

The EF-hand domain (C-terminal) containing 1 (EFHC1) gene, located on chromosome 6p12.3, encodes EFHC1 protein, which interacts with another protein that functions as a calcium channel. The EFHC1 protein has a role in neurotransmission, but may also have a role in apoptosis. Pathogenic variants in EFHC1 have been linked to juvenile myoclonic epilepsy.

FKRP

The fukutin related protein gene is located on chromosome 19q13.32. The protein encoded by this gene is fukutin related protein, its exact function is not known but it is important for cell migration in early brain development. FKRP gene abnormalities can cause Walker-Warburg syndrome - cobblestone lissencephaly, eye abnormality and myopathy.

FKTN

The fukutin gene is located on chromosome 9q31.2. The protein encoded by this gene is fukutin protein, its exact function is not known but it is important for cell migration in early brain development. FKTN gene abnormalities can cause Fukuyama congenital muscular dystrophy (seen almost exclusively in Japan) and Walker-Warburg syndrome. In both conditions, patients have cobblestone lissencephaly, eye abnormality and myopathy. However, patients with Walker-Warburg syndrome have a more severe presentation.

FLNA

The filamin A gene is located on chromosome Xq28. The protein encoded by this gene is filamin A, which works with other proteins forming the cytoskeleton, important for cell migration. FLNA gene abnormalities can cause periventricular nodular heterotopia.

FMR1 (FRAGILE X SYNDROME)

Fragile X syndrome is the most frequent cause of familial intellectual impairment and is the second most common cause of intellectual impairment after Down syndrome. Typical dysmorphic features (elongated face, large or protruding ears, and large testes) are recognized. Patients typically have autistic features. Epilepsy has been reported in up to 40% of patients. Seizures and EEG features are similar to those seen in self-limited epilepsy with centrotemporal spikes and related epilepsies. Seizures typically improve with age. The Fragile X abnormality is usually caused by a trinucleotide repeat expansion in the fragile X mental retardation 1 (FMR1) gene, located on chromosome Xq27.3. Diagnosis is determined by analysis of the number of trinucleotide repeats using polymerase chain reaction and methylation status using Southern blot analysis. This method does not detect missense pathogenic variants or deletions involving FMR1 and sequencing of the FMR1 gene may be required if there is clinical suspicion of Fragile X syndrome.

FOXG1

The forkhead box G1 (FOXG1) gene, located on chromosome 14q13, encodes a protein known as forkhead box G1 that acts as a transcription factor.

• Pathogenic variants in FOXG1 cause a congenital variant of Rett syndrome. In this syndrome severe intellectual impairment, microcephaly, jerky limb movements, epilepsy, and absent language development are apparent from early infancy. There is no early period of normal development.
• Duplications in the area of chromosome 14 that includes the FOXG1 gene may result in epileptic spasms or intractable seizures with developmental and intellectual impairment.

GABRA1

The gamma-aminobutyric acid (GABA) A receptor alpha 1 subunit (GABRA1) gene, located on chromosome 5q34, encodes the alpha 1 subunit of the GABA-A receptor. Variants in the GABRA1 gene have been linked to genetic/idiopathic generalized epilepsies such as juvenile myoclonic epilepsy.

GABRD

The gamma-aminobutyric acid (GABA) A receptor delta subunit (GABRD) gene, located on chromosome 1p36.3, encodes the delta subunit of the GABA-A receptor. Variants in the GABRD gene have been linked to genetic/idiopathic generalized epilepsies such as genetic epilepsy with febrile seizures plus and juvenile myoclonic epilepsy.

GABRG2

The gamma-aminobutyric acid (GABA) A receptor gamma 2 subunit (GABRG2) gene, located on chromosome 5q34, encodes the gamma 2 subunit of the GABA-A receptor. Variants in the GABRG2 gene have been linked to genetic/idiopathic generalized epilepsies such as childhood absence epilepsy, genetic epilepsy with febrile seizures plus spectrum and juvenile myoclonic epilepsy.

GLI3

The GLI family zinc finger 3 gene is located on chromosome 7p13. The protein encoded by this gene, GLI3 protein, is a transcription factor that controls gene expression, and is important in brain development. GLI3 gene abnormalities can cause hypothalamic hamartoma and/or polydactyly, and Pallister Hall syndrome.

GNAQ

The G protein subunit alpha q gene is located on chromosome 9q21. The protein encoded by this gene is a G protein that is important in cell signaling. GNAQ gene abnormalities can cause Sturge-Weber syndrome.

GRIN2A

The glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A) gene, located on chromosome 16p13.2, encodes a subunit of the N-methyl-D-aspartate (NMDA) receptor. Pathogenic variants in GRIN2A have been reported in self-limited epilepsy with centrotemporal spikes and developmental and/or epileptic encephalopathy with spike-wave activation in sleep.

KCNQ2

The potassium voltage-gated channel, KQT-like subfamily, member 2 (KCNQ2) gene, located on chromosome 20q13.3, encodes four alpha subunits of the potassium channel. KCNQ2 alpha subunits can interact with alpha subunits produced from the KCNQ3 gene to form a more functional potassium channel that transmits a much stronger M-current. Epilepsy syndromes seen with KCNQ2 pathogenic variants include self-limited (familial) neonatal epilepsy and early-infantile developmental and epileptic encephalopathy syndrome. Variants in specific regions of the KCNQ2 gene produce a dominant negative and more severe loss of potassium channel function in the latter syndrome. Seizures can respond partially or completely to sodium-channel blocking antiseizure medications. KCNQ2 early-infantile developmental and epileptic encephalopathy syndrome is considered an etiology-specific epilepsy syndrome

KCNQ3

The potassium voltage-gated channel, KQT-like subfamily, member 3 (KCNQ3) gene, located on chromosome 8q24, encodes four alpha subunits of the potassium channel. However, the four KCNQ3 alpha subunits can also interact with alpha subunits produced from the KCNQ2 gene to form a more functional potassium channel that transmits a much stronger M-current. KCNQ3 pathogenic variants are seen in self-limited (familial) neonatal epilepsy.

KCNT1

The potassium channel, subfamily T, member 1 (KCNT1) gene, located on chromosome 9q34.3, encodes a sodium-activated potassium channel subunit. Pathogenic variants in KCNT1 are found in more severe forms of sleep-related hypermotor (hyperkinetic) epilepsy and in epilepsy of infancy with migrating focal seizures.

LARGE

The like-glycosyltransferase gene is located on chromosome 22q12.3. The protein encoded by this gene is important for glycosylation of α-dystroglycan, and therefore for the cytoskeleton. LARGE gene abnormalities can cause Walker-Warburg syndrome - cobblestone lissencephaly, eye abnormality and myopathy.

LGI1

The leucine-rich, glioma inactivated 1 (LGI1) gene, located on chromosome 10q24, encodes a protein called leucine-rich, glioma inactivated 1 (Lgi1) or epitempin. This function of this gene product is as yet unknown. Pathogenic variants in LGI1 are found in autosomal dominant epilepsy with auditory features.

LIS1 (also known as PAFAH1B1)

The platelet activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1) gene, also known as the lissencephaly 1 (LIS1) gene, is located on chromosome 17p13.3. The protein encoded by this gene is a subunit of a complex called platelet activating factor acetyl hydrolase 1B. This regulates the level of platelet activating factor (PAF), which is important for normal microtubular function, and for neuronal migration in the developing brain. LIS1 (PAFAH1B1) gene abnormalities can cause lissencephaly - either in isolation, or as part of Miller Dieker syndrome.

MECP2

The methyl CpG binding protein 2 (MECP2) gene, located on chromosome Xq28, is responsible for the gene product MeCP2 protein. This protein plays an important role at synapses and may help regulate gene expression, but its exact function is unknown.

• A duplication of MECP2 results in MECP2 duplication syndrome - with intellectual impairment, developmental delay and epilepsy.
• Pathogenic variants in MECP2 are known to cause MECP2-related severe neonatal encephalopathy - neonates are males with microcephaly, movement disorders, breathing problems, and epilepsy.
• Eight particular pathogenic variants in MECP2 are responsible for nearly half of cases of PPM-X syndrome - affected individuals have psychiatric disorders, epilepsy, intellectual impairment and movement disorder (typically Parkinsonism). Males with this syndrome are more severely affected than females.
• More than 300 pathogenic variants in the MECP2 gene have been identified in females with Rett syndrome. In patients with Rett syndrome, epilepsy is seen in 80% of cases and is intractable in 30%. Generalized seizure types including generalized tonic-clonic, atypical absence, atonic, tonic and myoclonic seizures are recognized to occur in Rett syndrome.
• MECP2 pathogenic variants have also been reported in individuals with severe X-linked intellectual impairment, autism and a Rett-Angelman syndrome phenotype.

NPRL2

The NPR2-like, GATOR1 complex subunit gene is located on chromosome 3p21.31. The NPRL2 protein encoded by this gene contributes to the function of the GATOR 1 complex, inhibiting mTORC1 signaling, therefore controlling cell growth and differentiation. NPRL2 gene abnormalities have been found in patients with focal cortical dysplasia, including in familial cases.

NPRL3

The NPR3-like, GATOR1 complex subunit gene is located on chromosome 16p13.3. The NPRL3 protein encoded by this gene contributes to the function of the GATOR 1 complex, inhibiting mTORC1 signaling, therefore controlling cell growth and differentiation. NPRL3 gene abnormalities have been found in patients with focal cortical dysplasia, including in familial cases.

PCDH19

The protocadherin 19 (PCDH19) gene, located on chromosome Xq22.1, is responsible for a gene product that is a calcium-dependent cell-adhesion protein. This gene has been implicated in early-infantile developmental and epileptic encephalopathy syndrome and in a number of other epilepsies including genetic epilepsy with febrile seizures plus. PCDH19 pathogenic variants may be found in females with an epilepsy syndrome similar to Dravet syndrome (however myoclonic and absence seizures are typically not frequent), this epilepsy has been called epilepsy, female-restricted with mental retardation (EFMR). Seizures start early (mean age 9 months), are frequent, cluster, and are facilitated by fever. Seizure types include tonic-clonic, focal (often with evolution to focal to bilateral tonic-clonic seizures) and tonic (probably focal tonic) seizures. Development is often normal with regression at seizure onset in some; intellect varies from normal in a third to severe intellectual impairment. Autistic features and psychiatric disorders are prominent in severely affected girls. The X-linked mode of inheritance is remarkable, as normal transmitting fathers are hemizygous carriers and will pass the pathogenic variant (and clinical syndrome) to all their daughters, while half of the daughters of affected heterozygous mothers will inherit the pathogenic variant and clinical syndrome. Parental mosaicism of PCDH19 has also been described. The mechanism underlying this inheritance pattern is thought to be cellular interference, where two populations of cells (pathogenic variant positive and wild-type PCDH19) cannot form normal networks as PCDH19 has a key role in cell-cell adhesion. Family pedigrees, if the pathogenic variant is inherited, will reflect this inheritance pattern with epilepsy, intellectual impairment and/or psychiatric disorders limited to females. It should, however, be noted that there are rare reports of affected males with mosaicism. As de novo pathogenic variants are common, testing for PCDH19 should be considered in any female with fever aggravation of seizures, that have onset under 5 years of age.

PIK3CA

The phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene is located on chromosome 3q26.3. The protein encoded by this gene is important for the function of PI3K, a kinase that activates certain cell signaling molecules. These signaling molecules are important for cell growth, proliferation and migration. PIK3CA gene abnormality that is acquired in a mosaic fashion can cause megalencephaly-capillary malformation syndrome.

PIK3R2

The phosphoinositide-3-kinase regulatory subunit 2 gene is located on chromosome 19q13.2-q13.4. The protein encoded by this gene is important for the function of PI3K, a kinase that activates certain cell signaling molecules. These signaling molecules are important for cell growth, proliferation and migration. PIK3R2 gene abnormality can cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome.

PLCB1

The phospholipase C, beta 1 (phosphoinositide-specific) (PLCB1) gene, located on chromosome 20p12, encodes a protein that catalyzes the formation of inositol trisphosphate and diacylglycerol from phosphatidylinositol bisphosphate. Pathogenic variants in PLCB1 are found in early-infantile developmental and epileptic encephalopathy syndrome, patients may progress to have infantile epileptic spasm syndrome. Deletions in PLCB1 have been reported as a rare cause of epilepsy of infancy with migrating focal seizures.

PNKP

The polynucleotide kinase 3'-phosphatase (PNKP) gene, located on chromosome 19q13.3-q13.4, encodes a protein involved in DNA repair. Pathogenic variants in PNKP are found in early-infantile developmental and epileptic encephalopathy syndrome.

POMT1

The protein O-mannosyltransferase 1 gene is located on chromosome 9q34.1. The protein encoded by this gene is a subunit of the POMT enzyme complex, important for the normal functioning of α-dystroglycan, and therefore for the cytoskeleton. In skeletal muscles, α-dystroglycan helps stabilize and protect muscle fibers. In the brain, it is important for cell migration during early brain development. POMT1 gene abnormalities can cause Walker-Warburg syndrome (cobblestone lissencephaly, eye abnormality and myopathy) and muscle-eye brain disease.

POMT2

The protein O-mannosyltransferase 2 gene is located on chromosome 14q24. The protein encoded by this gene is a subunit of the POMT complex, important for the normal functioning of α-dystroglycan, and therefore for the cytoskeleton. In skeletal muscles, α-dystroglycan helps stabilize and protect muscle fibers. In the brain, it is important for cell migration during early brain development. POMT2 gene abnormalities can cause Walker-Warburg syndrome (cobblestone lissencephaly, eye abnormality and myopathy) and muscle-eye brain disease.

PRRT2

The proline-rich transmembrane protein 2 (PRRT2) gene, located on chromosome 16p11.2, encodes a transmembrane protein. Pathogenic variants in PRRT2 are found in self-limited infantile epilepsy and also in paroxysmal kinesigenic dyskinesia.

RELN

The reelin gene is located on chromosome 7q22. The protein encoded by this gene is reelin, this activates a signaling pathway in the developing brain that triggers neuronal migration to their proper locations. RELN gene abnormalities can cause lissencephaly with cerebellar hypoplasia.

SCN1A

The sodium channel, voltage-gated, type I, alpha subunit (SCN1A) gene, located on chromosome 2q24.3, has been implicated in a number of epilepsies. The SCN1A gene product is the alpha subunit of the NaV1.1 sodium channel. This sodium channel is important in controlling sodium transport into neurons. Over 150 pathogenic variants in the SCN1A gene have been linked to epilepsy. Epilepsies seen with SCN1A include genetic epilepsy with febrile seizures plus and Dravet syndrome. Febrile seizures may be the only clinical manifestation or pathogenic variants may be found in family members of individuals with epilepsy who do not have seizures. Specific pathogenic variants in SCN1A have also been associated with epilepsy of infancy with migrating focal seizures and familial hemiplegic migraine. Polymorphisms in this gene (ICS5N+5G>A polymorphism) may affect efficacy and adverse effects of sodium channel blocking anti-seizure medications.

SCN1B

The sodium channel, voltage-gated, type I, beta subunit (SCN1B) gene, located on chromosome 19q13.1, encodes the sodium channel beta-1 subunit. The sodium channel is important in controlling sodium transport into neurons. Epilepsies seen with SCN1B pathogenic variants include genetic epilepsy with febrile seizures plus. SCN1B pathogenic variants are also associated with risk of cardiac arrhythmia.

SCN2A

The sodium channel, voltage-gated, type II, alpha subunit (SCN2A) gene, located on chromosome 2q24.3, has been implicated in a number of epilepsies. The SCN2A gene product is the alpha subunit of the NaV1.1 sodium channel. This sodium channel is important in controlling sodium transport into neurons. Epilepsies seen with SCN2A pathogenic variants include self-limited familial neonatal-infantile epilepsy, self-limited familial infantile epilepsy, epilepsy of infancy with migrating focal seizures and early-infantile developmental and epileptic encephalopathy syndrome.

SLC2A1

The solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1) gene, located on chromosome 1p34.2, is responsible for a gene that encodes a major glucose transporter in the blood-brain barrier. Pathogenic variants in this gene can cause glucose transporter 1 deficiency syndrome and/or paroxysmal exercise induced dyskinesia.

SLC25A22

The solute carrier family 25 (mitochondrial carrier: glutamate), member 22 (SLC25A22) gene, located on chromosome 11p15.5, is responsible for a gene product that is a mitochondrial glutamate carrier. This gene has been implicated in Early-infantile DEE and early-infantile developmental and epileptic encephalopathy syndrome.

SPTAN1

The spectrin, alpha, non-erythrocytic 1 (SPTAN1) gene, located on chromosome 9q34.11, is responsible for the gene product alpha spectrin, a filamentous cytoskeletal protein that functions to stabilize plasma membranes and organize intracellular organelle. This gene has been implicated in early-infantile developmental and epileptic encephalopathy syndrome and in infantile epileptic spasm syndrome. Neuroimaging typically shows hypomyelination.

STXBP1

The syntaxin binding protein 1 (STXBP1) gene, located on chromosome 9q34.1, is responsible for the gene product syntaxin-binding protein, which plays a role in neurotransmitter release through modulation of synaptic vesicle docking and fusion. This gene has been implicated in early-infantile developmental and epileptic encephalopathy syndrome and in other epilepsies seen in individuals with intellectual impairment. STXBP1 pathogenic variants account for 10-15% of all cases of early-infantile developmental and epileptic encephalopathy syndrome. Neuroimaging typically shows hypomyelination.

TBC1D24

The TBC1 domain family, member 24 (TBC1D24) gene, located on chromosome 16p13.3, is a gene that may encode a protein that is GTPase-activating. TBC1D2 gene abnormalities have been linked to epilepsy of infancy with migrating focal seizures.

TCF4 (PITT HOPKIN SYNDROME)

The transcription factor 4 (TCF4) gene, located on chromosome 18q21.1, produces a transcription factor (TCF4 protein) that is part of the E-protein family. The TCF4 protein plays a role in the maturation of cells to carry out specific functions (cell differentiation) and the self-destruction of cells (apoptosis). At least 50 pathogenic variants in this gene have been found in Pitt Hopkin syndrome, a clinical syndrome with developmental delay, intellectual impairment (moderate-severe), epilepsy, distinct facial features (thin eyebrows, sunken eyes, prominent nose, high nasal bridge, a Cupid's bow appearance to the upper lip, a wide mouth with full lips, widely spaced teeth and thickened cupped ears) and breathing abnormality (typically a hyperventilation-apnoea sequence). Children typically have a happy demeanor, with frequent smiling and hand flapping.

TSC1

The tuberous sclerosis 1 gene is located on chromosome 9q34. The protein encoded by this gene is hamartin, which in combination with tuberin (see TSC2 gene) form a complex that is important in the mTOR pathway, an intracellular pathway that controls cell growth and differentiation. TSC1 gene abnormalities cause reduced mTOR inhibition and tuberous sclerosis.

TSC2

The tuberous sclerosis 2 gene is located on chromosome 16p13.3. The protein encoded by this gene is tuberin, which in combination with hamartin (see TSC1 gene) form a complex that is important in the mTOR pathway, an intracellular pathway that controls cell growth and differentiation. TSC2 gene abnormalities cause reduced mTOR inhibition and tuberous sclerosis. TSC2 gene abnormalities have also been found in DNA extracted from focal cortical dysplasia type IIB.

TUBA1A

The tubulin alpha 1a gene is located on chromosome 12q13.12. The protein encoded by this gene is α-tubulin, part of the tubulin family of proteins that are important for structure and function of microtubules - which in turn are important for cell migration in early brain development. TUBA1A gene abnormalities can cause lissencephaly and polymicrogyria.

WDR62

The WD repeat domain 62 gene is located on chromosome 19q13.12. The protein encoded by this gene is important for cell proliferation. WDR62 gene abnormalities can cause a wide variety of developmental brain malformations including lissencephaly and schizencephaly. Compound heterozygote gene abnormalities in WDR62 have been identified in patients with polymicrogyria. Patients have microcephaly and may have hypoplasia of the corpus callosum and cerebellum.

ZEB2 (MOWAT WILSON SYNDROME)

The zinc finger E-box binding homeobox 2 (ZEB2) gene, located on chromosome 2q22.3, produces the ZEB2 protein that controls early growth and development. It appears particularly important in embryonic neural crest tissues. At least 100 pathogenic variants in this gene have been found in Mowat Wilson syndrome, a clinical syndrome with developmental delay, intellectual impairment, epilepsy, distinct facial features (elongated square-shaped face, deep-set and widely spaced eyes, broad nasal bridge, rounded nasal tip, prominent jaw, pointed chin, large eyebrows, uplifted dimpled earlobes) and intestinal (Hirschsprung disease) and other (microcephaly, structural brain abnormality, cardiac) defects. Children typically have a happy demeanor, with frequent smiling open-mouthed expression.