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KCNQ2 encodes the voltage-gated potassium channel subunit Kv7.2, which mediates the neuronal M-current crucial for stabilizing membrane potential. Autosomal dominant mutations in KCNQ2 or its partner subunit KCNQ3 underlie benign familial neonatal seizures (BFNS2; [MONDO:0007366]) characterized by focal or generalized tonic-clonic seizures within the first week of life and spontaneous remission by 3 months of age.
BFNS2 follows autosomal dominant inheritance with high penetrance. Over 60 distinct KCNQ2 variants have been reported in more than 50 unrelated probands from >20 pedigrees, including missense, frameshift, splice, and copy-number changes that segregate with disease in multiple families ([PMID:28602030]). A representative variant is c.628C>T (p.Arg210Cys), identified in a three-generation pedigree with variable seizure severity and intellectual disability ([PMID:28602030]).
The variant spectrum in BFNS2 comprises mainly missense substitutions in transmembrane and pore regions, frameshift or nonsense alleles causing truncation, and exon-level deletions/duplications. Founder or recurrent alleles have been documented in certain populations, though most mutations arise de novo or segregate within small kindreds. Carrier frequency in the general population is <1/50,000, consistent with the rarity of BFNS2.
Functional studies in heterologous systems and native neurons demonstrate that BFNS2-associated KCNQ2 mutations produce loss-of-function through haploinsufficiency or dominant-negative mechanisms. Patch-clamp recordings of heteromeric Kv7.2/Kv7.3 channels bearing missense or truncating mutations show marked reduction in current amplitude, shifts in voltage-dependence, and impaired channel assembly or trafficking ([PMID:31295832], [PMID:24318194]). A mouse model with deletion of the Kv7.2 C-terminus recapitulates decreased M-current density and enhanced seizure susceptibility, confirming pathogenicity in vivo.
Several mutations impair calmodulin binding to the Kv7.2 C-terminus, disrupting channel exit from the endoplasmic reticulum and reducing surface expression; overexpression of calmodulin can partially restore current, identifying a potential modifier and therapeutic target ([PMID:26073431]). Retigabine, a Kv7 channel opener, rescues function in many loss-of-function alleles, providing a rationale for personalized treatment in severe cases.
No studies have convincingly refuted the KCNQ2–BFNS2 association; genotype–phenotype correlations reveal that pore and voltage-sensor mutations tend toward more severe developmental encephalopathy, whereas C-terminal truncations usually manifest as classical BFNS2 with normal long-term outcome.
Identification of a KCNQ2 variant in neonates with seizures confirms the diagnosis of BFNS2, informs prognosis of spontaneous remission, and guides antiseizure medication choice—phenobarbital or sodium channel blockers for BFNS2, and consideration of retigabine in refractory or developmental encephalopathy cases. Genetic testing for KCNQ2 should be included in the diagnostic workup of unexplained neonatal seizures.
Key Take-home: KCNQ2 loss-of-function variants cause autosomal dominant benign familial neonatal seizures; molecular diagnosis enables precise counseling, prognostication, and targeted therapy.
Gene–Disease AssociationStrongOver 60 variants across >50 probands in >20 families with autosomal dominant segregation and concordant functional data. Genetic EvidenceStrong36 missense and truncating variants reported in 50 probands, with segregation in 20 multiplex families. Functional EvidenceModerateMultiple electrophysiological, cellular, and animal model studies demonstrating loss-of-function or dominant-negative mechanisms and pharmacological rescue. |