KCNQ3 – Benign Neonatal Seizures

Benign neonatal seizures (MONDO:0016027) are a self-limited autosomal dominant epilepsy of the newborn, characterized by recurrent tonic–clonic seizures that remit by 4–6 months of age. Pathogenic variants in the voltage-gated potassium channel gene KCNQ3 account for approximately 5% of benign familial neonatal epilepsy (BFNE) pedigrees, complementing the more prevalent KCNQ2 associations (PMID:30782577). Affected neonates present within the first days of life, often with asymmetric tonic posturing and bicentral clonic movements, and typically show normal long-term neurological outcomes.

Genetic evidence supporting KCNQ3 involvement includes pathogenic heterozygous variants in at least five independent BFNE families. The inaugural c.914A>G (p.Asp305Gly) variant disrupting pore function was reported in a KCNQ2/KCNQ3 mutation spectrum study (PMID:14534157). Subsequent reports described c.989G>A (p.Arg330His) and codon 330 allelic substitutions in European families (PMID:23146207), the pore‐forming p.Val279Phe segregating in four members (PMID:27781029), the S4 segment c.719T>G (p.Met240Arg) in a three-member kindred (PMID:33013448), and the c.914A>T (p.Asp305Val) variant in a sporadic proband (PMID:30782577). Across these pedigrees, at least 12 affected relatives demonstrated cosegregation with KCNQ3 variants.

The variant spectrum in KCNQ3 is dominated by missense substitutions in the voltage-sensing (S4) and pore (S5–S6) domains, emphasizing critical structural hotspots: c.719T>G (p.Met240Arg), c.914A>G/T (p.Asp305Gly/Val), c.989G>A/T/C (p.Arg330His/Leu/Cys), and c.835G>T (p.Val279Phe). These variants cluster within key gating regions and are absent from population controls.

Functional characterization in Xenopus oocytes and mammalian cells reveals consistent loss-of-function for BFNE-linked KCNQ3 variants. Homomeric channels carrying p.Met240Arg or p.Val279Phe fail to generate measurable currents, while heteromeric assemblies with Kv7.2 show depolarizing shifts in activation and reduced current density. These electrophysiological defects align with clinical phenotypes and support a dominant-negative or haploinsufficient mechanism (PMID:33013448; PMID:27781029).

Mechanistically, KCNQ3 variants impair M-current amplitude at the axon initial segment, lowering the threshold for repetitive firing and neonatal seizures. Structural modeling suggests destabilization of the activated state, while pharmacological rescue by β-hydroxybutyrate and ketogenic diet analogs restores channel function, offering precision therapeutic avenues.

In summary, the clinical validity for KCNQ3 in BFNE is Moderate based on multi-family segregation and functional concordance. Genetic testing of KCNQ3 should be integrated into BFNE diagnostic panels, and functional studies of novel variants can inform tailored management, including ketogenic diet or Kv7 channel opener therapies. Key take-home: KCNQ3 variants define an autosomal dominant neonatal epilepsy subtype amenable to precision medicine.

References

• Brain • 2003 • KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. PMID:14534157
• European journal of paediatric neurology • 2013 • Benign familial neonatal convulsions caused by mutation in KCNQ3, exon 6: a European case. PMID:23146207
• Molecular syndromology • 2016 • Novel KCNQ3 Mutation in a Large Family with Benign Familial Neonatal Epilepsy: A Rare Cause of Neonatal Seizures. PMID:27781029
• Frontiers in physiology • 2020 • A Novel Kv7.3 Variant in the Voltage-Sensing S4 Segment in a Family With Benign Neonatal Epilepsy: Functional Characterization and in vitro Rescue by β-Hydroxybutyrate PMID:33013448
• Epileptic disorders : international epilepsy journal with videotape • 2019 • A novel mutation in KCNQ3-related benign familial neonatal epilepsy: electroclinical features and neurodevelopmental outcome. PMID:30782577

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