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KCNA2 encodes the voltage-gated potassium channel Kv1.2, which is critical for neuronal repolarization. Heterozygous variants in KCNA2 have been repeatedly identified in patients with developmental and epileptic encephalopathy (DEE) across multiple independent cohorts, with onset typically in infancy and childhood, supporting a strong gene-disease relationship ([PMID:30292882]).
Autosomal dominant inheritance is established by de novo occurrence in the majority of cases. Initial reports include one patient with c.982T>G (p.Leu328Val) ([PMID:30292882]) and a multi-generation family segregating an in-frame deletion c.765_773del (p.255_257del) in seven affected relatives ([PMID:27733563]). A cohort of 23 DEE patients carrying 11 KCNA2 variants demonstrated de novo origin in 20 individuals ([PMID:29050392]), and seven more probands with novel p.Pro407Ala and p.Tyr417Cys variants expanded the spectrum ([PMID:33802230]). Five additional DEE cases with electrical status epilepticus during sleep were attributed to KCNA2 variants in 5/74 tested cases ([PMID:33897753]).
The phenotypic spectrum includes severe early-onset epilepsy with focal or generalized seizures, developmental delay or intellectual disability, cerebellar ataxia, episodic ataxia, and complicated hereditary spastic paraplegia, indicating a continuous clinical continuum ([PMID:33802230]; [PMID:33897753]). Epileptic encephalopathy frequently precedes or co-occurs with ataxia, reflecting mixed gain- and loss-of-function effects at the channel level.
Functional studies consistently show that pathogenic KCNA2 variants exert dominant-negative loss-of-function, gain-of-function, or mixed biophysical defects. Voltage-clamp assays in Xenopus oocytes revealed dominant-negative suppression of current for p.255_257del and p.Arg297Gln ([PMID:27733563]), while molecular dynamics and voltage-clamp fluorometry of p.Phe302Leu demonstrated altered voltage-sensor exposure and accelerated activation/inactivation kinetics ([PMID:32833227]). Two variants at His310 had opposite functional outcomes in human KV1.2 channels, confirming position-specific effects ([PMID:37883018]). Patient-derived induced pluripotent stem cell models carrying p.Leu328Val and p.Leu290Arg recapitulate channel dysfunction and support pathogenicity in a human neuronal context ([PMID:30292882]; [PMID:32540721]).
A large case-control pharmacogenetic study found no association of common KCNA2 polymorphisms with susceptibility or drug resistance in genetic generalized epilepsy, suggesting that rare de novo variants, rather than common alleles, drive DEE risk ([PMID:28658141]). No current evidence refutes the role of rare KCNA2 variants in DEE.
Collectively, the convergence of de novo variant occurrence in >35 probands across four independent cohorts, familial segregation, detailed genotype-phenotype correlations, and robust functional concordance establishes a strong and clinically actionable association between KCNA2 and developmental and epileptic encephalopathy. KCNA2 testing should be considered in patients with early-onset DEE, and variant-specific functional data may inform precision therapies.
Gene–Disease AssociationStrong~36 probands including 20 de novo cases; multi-cohort evidence and functional concordance Genetic EvidenceStrongHeterozygous de novo and recurrent variants (n≈36 probands), including one in-frame deletion segregating in a multi-generational family ([PMID:27733563]) Functional EvidenceStrongMultiple in vitro electrophysiological and molecular modeling studies for >10 variants demonstrate dominant-negative, gain- and loss-of-function effects concordant with clinical phenotypes; iPSC models replicate patient mutation impact |