Lennox-Gastaut syndrome: genes and variants

Genes linked to Lennox-Gastaut syndrome

• CCND2: G1/S-specific cyclin-D2

  It promotes G1-to-S cell-cycle progression through activation of CDK4 and CDK6 and is important in proliferating neural and endocrine tissues. Activating germline variants can cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, while overexpression occurs in several cancers.

  1 disease-causing and 0 uncertain variants in CCND2 are linked to Lennox-Gastaut syndrome.

• DNM1: Dynamin-1

  It drives membrane fission during synaptic-vesicle endocytosis, allowing rapid recycling of vesicles after neurotransmitter release. De novo pathogenic variants can cause severe developmental and epileptic encephalopathy with profound developmental impairment.

  0 disease-causing and 0 uncertain variants in DNM1 are linked to Lennox-Gastaut syndrome.

• CA2: Carbonic anhydrase 2

  It rapidly interconverts carbon dioxide and bicarbonate, supporting acid-base balance, renal acidification, respiration, bone remodeling, and fluid secretion. Biallelic loss-of-function variants cause carbonic anhydrase II deficiency, with osteopetrosis, renal tubular acidosis, and cerebral calcification.

  0 disease-causing and 0 uncertain variants in CA2 are linked to Lennox-Gastaut syndrome.

• GABRA1: Gamma-aminobutyric acid receptor subunit alpha-1

  The gene product supplies the alpha-1 subunit of a pentameric GABA-A receptor, a ligand-gated chloride channel in the brain. GABA binding allows chloride influx that dampens neuronal activity, making this receptor important for inhibition and seizure biology.

  0 disease-causing and 0 uncertain variants in GABRA1 are linked to Lennox-Gastaut syndrome.

• GABRB3: Gamma-aminobutyric acid receptor subunit beta-3

  It contributes to inhibitory GABA-A receptor currents in the brain and is particularly important during neurodevelopment. Pathogenic variants can cause developmental and epileptic encephalopathy, while altered dosage within chromosome 15q11-q13 contributes to neurodevelopmental disorders.

  0 disease-causing and 0 uncertain variants in GABRB3 are linked to Lennox-Gastaut syndrome.

• 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 0 uncertain variants in GABRG2 are linked to Lennox-Gastaut syndrome.

• GRIA1: Glutamate receptor 1

  An AMPA-type glutamate receptor subunit that forms a ligand-gated cation channel at excitatory synapses. Glutamate opens the receptor to convert a chemical signal into an electrical response, supporting fast transmission and activity-dependent plasticity in the brain.

  0 disease-causing and 0 uncertain variants in GRIA1 are linked to Lennox-Gastaut syndrome.

• GRIA2: Glutamate receptor 2

  An AMPA-type glutamate receptor subunit that contributes to fast excitatory signaling in the nervous system. Together with other subunits it forms a glutamate-gated cation channel, and its presence helps shape the channel's ion permeability and synaptic behavior.

  0 disease-causing and 0 uncertain variants in GRIA2 are linked to Lennox-Gastaut syndrome.

• SCN10A: Sodium channel protein type 10 subunit alpha

  The protein forms Nav1.8, a tetrodotoxin-resistant voltage-gated sodium channel found in excitable membranes. It helps generate sensory-neuron electrical signals and is especially important in mechanisms of neuropathic pain and inherited episodic pain.

  0 disease-causing and 0 uncertain variants in SCN10A are linked to Lennox-Gastaut syndrome.

• 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.

  0 disease-causing and 0 uncertain variants in SCN1A are linked to Lennox-Gastaut syndrome.

• 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 0 uncertain variants in SCN2A are linked to Lennox-Gastaut syndrome.

• 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 Lennox-Gastaut syndrome.

• SCN9A: Sodium channel protein type 9 subunit alpha

  The protein forms Nav1.7, a voltage-gated sodium channel that amplifies electrical signals in peripheral sensory neurons. Changes in Nav1.7 activity can produce either excessive pain or congenital insensitivity to pain, making SCN9A central to pain biology.

  0 disease-causing and 0 uncertain variants in SCN9A are linked to Lennox-Gastaut syndrome.

Weakly linked (only a few uncertain records): GRIN2B.

Known disease-causing variants in Lennox-Gastaut syndrome

Same protein, different disease

• Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 is also caused by CCND2 variants; they fall partly in the same places as the Lennox-Gastaut syndrome variants (7 disease-causing).

Diseases related to Lennox-Gastaut syndrome

• Epilepsy, also linked to CA2, GABRA1, GABRB3, GABRG2 and 7 more
• Amyotrophic lateral sclerosis, also linked to SCN10A, SCN1A, SCN2A, SCN8A and 1 more
• Cardiac arrhythmia, also linked to SCN10A, SCN1A, SCN2A, SCN8A and 1 more
• Focal epilepsy, also linked to SCN10A, SCN1A, SCN2A and SCN9A
• Genetic developmental and epileptic encephalopathy, also linked to GABRG2, SCN1A, SCN2A and SCN8A
• Generalized epilepsy with febrile seizures plus, also linked to GABRG2, SCN1A and SCN9A
• EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 2, also linked to GABRA1, GABRB3 and GABRG2
• Early-infantile DEE, also linked to SCN1A and SCN8A
• Seizures, benign familial infantile, 3, also linked to SCN2A and SCN8A
• Complex neurodevelopmental disorder, also linked to SCN2A and SCN8A
• Febrile seizures, familial, 3a, also linked to GABRG2 and SCN1A
• Self-limited epilepsy with centrotemporal spikes, also linked to GABRG2 and SCN2A

Frequently asked questions

Which genes are linked to Lennox-Gastaut syndrome?

In CATVariant, Lennox-Gastaut syndrome is linked to 13 analyzed proteins: CCND2 (G1/S-specific cyclin-D2), DNM1 (Dynamin-1), CA2 (Carbonic anhydrase 2), GABRA1 (Gamma-aminobutyric acid receptor subunit alpha-1), GABRB3 (Gamma-aminobutyric acid receptor subunit beta-3), GABRG2 (Gamma-aminobutyric acid receptor subunit gamma-2) and 7 more.

How many genetic variants are linked to Lennox-Gastaut syndrome?

101 variants: 1 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 0 are of uncertain significance or have conflicting reports.

Which uncertain variants in Lennox-Gastaut syndrome 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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