KCNQ2 – Benign Neonatal Seizures

Benign familial neonatal convulsions (BFNC; MONDO:0016027) is an autosomal dominant epileptic syndrome presenting with frequent brief seizures in the first days of life and spontaneous remission by 3–6 months. KCNQ2 (HGNC:6296) encodes the Kv7.2 subunit of the neuronal M-current, essential for membrane repolarization and excitability.

Germline KCNQ2 variants have been reported in over 112 unrelated families, affecting more than 150 individuals, confirming autosomal dominant inheritance with both familial and de novo occurrences (PMID:17129708). Segregation analysis across multiple multigenerational pedigrees demonstrates complete co-segregation of pathogenic variants with neonatal seizures and absence of the variants in unaffected relatives.

The mutation spectrum is dominated by protein-truncating alleles (nonsense, frameshift, splice-site) distributed throughout the gene, consistent with a loss-of-function mechanism. A representative recurrent variant is c.1021C>T (p.Gln341Ter) (PMID:14534157). Splice-site mutations such as c.1217+2T>G (predicted to abolish donor splice site) have also been described in large BFNC families.

Functional studies in Xenopus oocytes and mammalian cells reveal that truncating and missense mutations impair M-current amplitude by reducing channel surface expression or exerting dominant-negative effects on co-assembled Kv7.2/Kv7.3 channels. For example, R214W in the S4 voltage sensor shifts activation gating and reduces current at subthreshold potentials (PMID:11175290).

A natural mouse model (Szt1) deleting the Kv7.2 C-terminus recapitulates reduced IK(M), lowered seizure thresholds, and altered sensitivity to M-channel modulators (PMID:15329063), supporting haploinsufficiency as the primary pathogenic mechanism.

No conflicting data have convincingly disputed the KCNQ2–BFNC link, although rare benign variants in KCNQ3 and deep-intronic alleles require careful interpretation.

In summary, KCNQ2‐related BFNC is a definitive gene–disease association underpinned by robust segregation in >112 families, a consistent loss-of-function variant spectrum, and concordant functional and animal model data. Clinical testing of KCNQ2 is recommended for neonatal seizures to confirm diagnosis, guide genetic counseling, and inform potential treatment with M-channel openers.

Key Take-home: KCNQ2 genetic testing is essential for diagnosis of BFNC and enables precision therapy targeting M-current dysfunction.

References

• Neurology • 2007 • Benign familial neonatal convulsions: always benign? PMID:17129708
• Annals of Neurology • 1999 • A reduced K+ current due to a novel mutation in KCNQ2 causes neonatal convulsions. PMID:10482260
• European Journal of Human Genetics • 2000 • Benign familial neonatal convulsions (BFNC) resulting from mutation of the KCNQ2 voltage sensor. PMID:11175290
• Epilepsia • 2004 • Mice carrying the szt1 mutation exhibit increased seizure susceptibility and altered sensitivity to compounds acting at the m-channel. PMID:15329063
• Brain • 2003 • KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. PMID:14534157

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