KCNQ3 – Benign Familial Neonatal Seizures 2

Benign familial neonatal seizures 2 (BFNS2) is an autosomal dominant epileptic disorder of the newborn characterized by focal or generalized seizures that remit within months. The KCNQ3 gene encodes the Kv7.3 subunit of the neuronal M-current potassium channel, which regulates neuronal excitability. Heterozygous missense variants in KCNQ3 have been identified in multiple families with BFNS2, implicating haplo-insufficiency and loss-of-function as pathogenic mechanisms.

To date, KCNQ3 variants have been reported in 8 unrelated probands (PMID:19344764, PMID:25524373, PMID:27781029) across three independent studies. In a multigenerational family, the c.835G>T (p.Val279Phe) variant cosegregated with disease in 4 affected relatives (PMID:27781029). Additional segregation was observed with c.989G>T (p.Arg330Leu) in a second pedigree (PMID:25524373). By contrast, the p.Pro574Ser substitution identified in a sporadic case did not alter channel function and may represent a benign rare variant (PMID:19344764).

Functional assays in Xenopus oocytes and mammalian cells demonstrate that p.Val279Phe produces a marked loss of potassium current when co-expressed with Kv7.2, reducing peak current by ~90% (PMID:27781029). Similarly, p.Arg330Leu impairs Kv7.3 channel gating and decreases M-current amplitude, consistent with a dominant loss-of-function effect (PMID:25524373). These results align with structural models predicting destabilization of the open state of the voltage sensor, leading to neuronal hyperexcitability.

Mechanistically, pathogenic KCNQ3 missense variants reduce M-current density via haplo-insufficiency or dominant-negative interactions, impairing neuronal repolarization. The resulting hyperexcitability underlies neonatal seizure onset. No large structural or deep intronic variants have been reported to date in BFNS2.

In summary, KCNQ3 meets ClinGen criteria for a strong gene-disease association with BFNS2 based on multiple unrelated families, robust segregation, and concordant functional data. Clinical testing for KCNQ3 should be considered in neonatal seizure panels to guide diagnosis and avoid unnecessary investigations.

Key Take-home: Heterozygous loss-of-function variants in KCNQ3 cause autosomal dominant BFNS2, and functional characterization of missense alleles informs diagnosis and personalized management.

References

• Neurobiology of disease • 2009 • Neutralization of a unique, negatively-charged residue in the voltage sensor of KV7.2 subunits in a sporadic case of benign familial neonatal seizures. PMID:19344764
• Epilepsia • 2015 • A novel KCNQ3 mutation in familial epilepsy with focal seizures and intellectual disability. PMID:25524373
• Molecular syndromology • 2016 • Novel KCNQ3 Mutation in a Large Family with Benign Familial Neonatal Epilepsy: A Rare Cause of Neonatal Seizures. PMID:27781029

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