Genetic developmental and epileptic encephalopathy: genes and variants

Genes linked to Genetic developmental and epileptic encephalopathy

• SCN1A: Sodium channel protein type 1 subunit alpha

  Its sodium current is especially important for reliable firing of inhibitory interneurons and therefore for balancing excitation across neural networks. Loss-of-function variants are the major cause of Dravet syndrome, while other variants cause GEFS+ or familial hemiplegic migraine.

  2 disease-causing and 0 uncertain variants in SCN1A are linked to Genetic developmental and epileptic encephalopathy.

• PPP2R5D: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform

  It directs the PP2A phosphatase toward specific signaling substrates in neurons and other cells, helping control phosphorylation-dependent growth and synaptic pathways. De novo pathogenic variants cause Jordan's syndrome, with developmental delay, intellectual disability, hypotonia, and often macrocephaly.

  1 disease-causing and 1 uncertain variants in PPP2R5D are linked to Genetic developmental and epileptic encephalopathy.

• HCN1: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1

  The protein forms a hyperpolarization-activated channel that conducts both potassium and sodium ions. It contributes to pacemaker currents and the neuronal I(h) current that shapes excitability, and HCN1 variants are associated with developmental epilepsy syndromes.

  0 disease-causing and 0 uncertain variants in HCN1 are linked to Genetic developmental and epileptic encephalopathy.

• KCNQ2: Potassium voltage-gated channel subfamily KQT member 2

  Together with KCNQ3, its slowly activating potassium current provides much of the neuronal M-current that suppresses repetitive firing. Pathogenic variants cause a spectrum from self-limited familial neonatal epilepsy to severe developmental and epileptic encephalopathy.

  0 disease-causing and 0 uncertain variants in KCNQ2 are linked to Genetic developmental and epileptic encephalopathy.

• STXBP1: Syntaxin-binding protein 1

  It controls SNARE-complex assembly and synaptic-vesicle fusion, making it essential for rapid neurotransmitter release. Haploinsufficiency causes STXBP1-related neurodevelopmental disorder with developmental impairment, epilepsy, movement abnormalities, and intellectual disability.

  0 disease-causing and 0 uncertain variants in STXBP1 are linked to Genetic developmental and epileptic encephalopathy.

• ATP6V1A: V-type proton ATPase catalytic subunit A

  It provides ATP-hydrolyzing activity to the vacuolar proton pump, driving acidification of endosomes, lysosomes, and secretory vesicles. De novo pathogenic variants can cause developmental encephalopathy with epilepsy and intellectual disability.

  0 disease-causing and 0 uncertain variants in ATP6V1A are linked to Genetic developmental and epileptic encephalopathy.

• CACNA1E: Voltage-dependent R-type calcium channel subunit alpha-1E

  It contributes R-type calcium current at neuronal membranes and presynaptic terminals, shaping neurotransmitter release and neuronal firing. De novo pathogenic variants can cause severe developmental and epileptic encephalopathy with movement abnormalities.

  0 disease-causing and 2 uncertain variants in CACNA1E are linked to Genetic developmental and epileptic encephalopathy.

• NTRK2: BDNF/NT-3 growth factors receptor

  BDNF and neurotrophin-4 signaling through this pathway promotes neuronal survival, synaptic plasticity, and circuit maturation. Rare germline variants can cause neurodevelopmental or metabolic phenotypes, while oncogenic NTRK2 fusions can drive diverse cancers.

  0 disease-causing and 0 uncertain variants in NTRK2 are linked to Genetic developmental and epileptic encephalopathy.

• SYNJ1: Polyphosphatidylinositol phosphatase SYNJ1

  It remodels phosphoinositides during clathrin-mediated synaptic-vesicle recycling and helps nerve terminals rapidly regenerate release-ready vesicles. Biallelic pathogenic variants can cause early-onset parkinsonism or severe developmental and epileptic encephalopathy.

  0 disease-causing and 0 uncertain variants in SYNJ1 are linked to Genetic developmental and epileptic encephalopathy.

• GABRG2: Gamma-aminobutyric acid receptor subunit gamma-2

  The gene product supplies the gamma-2 subunit of synaptic GABA-A receptors, which are pentameric chloride channels activated by the inhibitory neurotransmitter GABA. The subunit helps receptor assembly and localization at neuronal membranes, and GABRG2 variants are associated with several epilepsy syndromes.

  0 disease-causing and 2 uncertain variants in GABRG2 are linked to Genetic developmental and epileptic encephalopathy.

• SCN2A: Sodium channel protein type 2 subunit alpha

  The protein forms Nav1.2, a voltage-gated sodium channel that carries sodium current during neuronal action potentials. By shaping neuronal excitability and signal propagation, it supports brain circuits involved in development, learning, and seizure susceptibility.

  0 disease-causing and 1 uncertain variants in SCN2A are linked to Genetic developmental and epileptic encephalopathy.

• CACNA2D2: Voltage-dependent calcium channel subunit alpha-2/delta-2

  It promotes trafficking and functional expression of voltage-gated calcium-channel complexes and is particularly important in cerebellar neurons. Biallelic loss-of-function variants can cause developmental epileptic encephalopathy with cerebellar atrophy and ataxia.

  0 disease-causing and 0 uncertain variants in CACNA2D2 are linked to Genetic developmental and epileptic encephalopathy.

• KCNA2: Potassium voltage-gated channel subfamily A member 2

  Its current helps repolarize neuronal membranes and regulate action-potential firing and neurotransmitter release. Both loss- and gain-of-function variants can cause developmental and epileptic encephalopathy, often with ataxia, movement abnormalities, or intellectual disability.

  0 disease-causing and 0 uncertain variants in KCNA2 are linked to Genetic developmental and epileptic encephalopathy.

• KCNB1: Potassium voltage-gated channel subfamily B member 1

  Its delayed-rectifier current contributes to neuronal repolarization and also participates in activity-dependent signaling complexes at the membrane. De novo pathogenic variants are an important cause of developmental and epileptic encephalopathy with intellectual disability and variable seizures.

  0 disease-causing and 0 uncertain variants in KCNB1 are linked to Genetic developmental and epileptic encephalopathy.

• SCN8A: Sodium channel protein type 8 subunit alpha

  The protein forms Nav1.6, a voltage-gated sodium channel that sets the threshold and propagation of neuronal action potentials. It is widely important for neuronal excitability, and SCN8A variants are associated with developmental and epileptic encephalopathies.

  0 disease-causing and 0 uncertain variants in SCN8A are linked to Genetic developmental and epileptic encephalopathy.

Weakly linked (only a few uncertain records): ANGPTL3, CEP290, CHD8, RYR3, SETD2 and ZFHX3.

Known disease-causing variants in Genetic developmental and epileptic encephalopathy

Same protein, different disease

• Early-infantile DEE is also caused by SCN1A variants; they fall mostly in different places as the Genetic developmental and epileptic encephalopathy variants (422 disease-causing).
• Severe myoclonic epilepsy in infancy is also caused by SCN1A variants; they fall mostly in different places as the Genetic developmental and epileptic encephalopathy variants (213 disease-causing).
• Generalized epilepsy with febrile seizures plus is also caused by SCN1A variants; they fall mostly in different places as the Genetic developmental and epileptic encephalopathy variants (76 disease-causing).
• Migraine, familial hemiplegic, 1 is also caused by SCN1A variants; they fall mostly in different places as the Genetic developmental and epileptic encephalopathy variants (20 disease-causing).
• Autosomal dominant epilepsy is also caused by SCN1A variants; they fall mostly in different places as the Genetic developmental and epileptic encephalopathy variants (4 disease-causing).
• Houge-Janssens syndrome 1 is also caused by PPP2R5D variants; they fall mostly in different places as the Genetic developmental and epileptic encephalopathy variants (14 disease-causing).

Diseases related to Genetic developmental and epileptic encephalopathy

• Epilepsy, also linked to CACNA1E, CACNA2D2, GABRG2, KCNQ2 and 4 more
• Early-infantile DEE, also linked to CACNA2D2, HCN1, KCNQ2, SCN1A and 2 more
• Lennox-Gastaut syndrome, also linked to GABRG2, SCN1A, SCN2A and SCN8A
• Undetermined early-onset epileptic encephalopathy, also linked to HCN1, KCNA2, KCNB1 and SCN8A
• Amyotrophic lateral sclerosis, also linked to SCN1A, SCN2A and SCN8A
• Generalized epilepsy with febrile seizures plus, also linked to GABRG2, HCN1 and SCN1A
• Cardiac arrhythmia, also linked to SCN1A, SCN2A and SCN8A
• Complex neurodevelopmental disorder, also linked to KCNA2, SCN2A and SCN8A
• Severe myoclonic epilepsy in infancy, also linked to HCN1 and SCN1A
• Seizures, benign familial infantile, 3, also linked to SCN2A and SCN8A
• Febrile seizures, familial, 3a, also linked to GABRG2 and SCN1A
• West syndrome, also linked to KCNQ2 and SCN2A

Frequently asked questions

Which genes are linked to Genetic developmental and epileptic encephalopathy?

In CATVariant, Genetic developmental and epileptic encephalopathy is linked to 15 analyzed proteins: SCN1A (Sodium channel protein type 1 subunit alpha), PPP2R5D (Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform), HCN1 (Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1), KCNQ2 (Potassium voltage-gated channel subfamily KQT member 2), STXBP1 (Syntaxin-binding protein 1), ATP6V1A (V-type proton ATPase catalytic subunit A) and 9 more.

How many genetic variants are linked to Genetic developmental and epileptic encephalopathy?

275 variants: 3 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 9 are of uncertain significance or have conflicting reports.

Which uncertain variants in Genetic developmental and epileptic encephalopathy look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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