Undetermined early-onset epileptic encephalopathy: genes and variants

Genes linked to Undetermined early-onset 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.

  1 disease-causing and 0 uncertain variants in SCN8A are linked to Undetermined early-onset 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 Undetermined early-onset 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 Undetermined early-onset epileptic encephalopathy.

• WWOX: WW domain-containing oxidoreductase

  It participates in cellular stress, metabolism, and transcriptional signaling and spans a common fragile site frequently altered in cancer. Biallelic loss-of-function variants cause severe developmental and epileptic encephalopathy or spinocerebellar ataxia, depending on residual function.

  0 disease-causing and 0 uncertain variants in WWOX are linked to Undetermined early-onset 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 Undetermined early-onset epileptic encephalopathy.

Known disease-causing variants in Undetermined early-onset epileptic encephalopathy

Same protein, different disease

• Early-infantile DEE is also caused by SCN8A variants; they fall mostly in different places as the Undetermined early-onset epileptic encephalopathy variants (90 disease-causing).
• Cognitive impairment with or without cerebellar ataxia is also caused by SCN8A variants; they fall mostly in different places as the Undetermined early-onset epileptic encephalopathy variants (22 disease-causing).
• Seizures, benign familial infantile, 3 is also caused by SCN8A variants; they fall mostly in different places as the Undetermined early-onset epileptic encephalopathy variants (12 disease-causing).
• Complex neurodevelopmental disorder is also caused by SCN8A variants; they fall mostly in different places as the Undetermined early-onset epileptic encephalopathy variants (8 disease-causing).
• Autosomal recessive inheritance is also caused by SCN8A variants; they fall mostly in different places as the Undetermined early-onset epileptic encephalopathy variants (3 disease-causing).

Diseases related to Undetermined early-onset epileptic encephalopathy

• Genetic developmental and epileptic encephalopathy, also linked to HCN1, KCNA2, KCNB1 and SCN8A
• Early-infantile DEE, also linked to HCN1 and SCN8A
• Complex neurodevelopmental disorder, also linked to KCNA2 and SCN8A
• Severe myoclonic epilepsy in infancy, also linked to HCN1
• Seizures, benign familial infantile, 3, also linked to SCN8A
• Amyotrophic lateral sclerosis, also linked to SCN8A
• Generalized epilepsy with febrile seizures plus, also linked to HCN1
• Cardiac arrhythmia, also linked to SCN8A
• Cognitive impairment with or without cerebellar ataxia, also linked to SCN8A
• Epilepsy, also linked to SCN8A
• Fetal akinesia deformation sequence, also linked to SCN8A
• Autosomal recessive spinocerebellar ataxia 12, also linked to WWOX

Frequently asked questions

Which genes are linked to Undetermined early-onset epileptic encephalopathy?

In CATVariant, Undetermined early-onset epileptic encephalopathy is linked to 5 analyzed proteins: SCN8A (Sodium channel protein type 8 subunit alpha), KCNB1 (Potassium voltage-gated channel subfamily B member 1), KCNA2 (Potassium voltage-gated channel subfamily A member 2), WWOX (WW domain-containing oxidoreductase) and HCN1 (Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1).

How many genetic variants are linked to Undetermined early-onset epileptic encephalopathy?

386 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 Undetermined early-onset 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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