KCNQ2 – Benign Familial Infantile Epilepsy

Benign familial infantile epilepsy (BFIE) is an autosomal dominant, self-limited epilepsy characterized by clusters of focal or generalized seizures beginning between 3 and 12 months of age and often remitting by 2 years without neurodevelopmental sequelae. The condition shows incomplete penetrance and familial segregation, with causative genes encoding neuronal M-type potassium channel subunits.

Clinical Validity: KCNQ2 (HGNC:6296) variants have been reported in multiple small families with BFIE. In a Chinese cohort of 79 families (4 BFNE, 7 BFNIE, 68 BFIE), targeted sequencing identified KCNQ2 mutations in 9 families, including 3 of 68 BFIE kindreds, confirming a role in BFIE (3 families) (PMID:29215089). The number of unrelated probands with BFIE-linked KCNQ2 variants supports a Moderate level of evidence.

Genetic Evidence: BFIE due to KCNQ2 follows autosomal dominant inheritance. Three unrelated BFIE families harbored frameshift or truncating KCNQ2 alleles, and cosegregation was observed within each pedigree (PMID:29215089). The variant spectrum includes truncating, splice, and missense changes. A representative allele is c.2007dup (p.Tyr670fs) (PMID:29215089). A separate familial BFIE pedigree carrying the pore-helix variant c.812G>T (p.Gly271Val) further exemplifies segregation across generations (PMID:26835270).

Functional Evidence: BFIE-associated KCNQ2 variants display loss-of-function effects in heterologous systems, consistent with haploinsufficiency. The p.Gly271Val mutant shows ~75% reduction of M-current and slowed activation kinetics in HEK293 cells, with retigabine partially restoring current amplitude (PMID:26835270). Additional electrophysiological studies of BFIE-linked missense and truncating KCNQ2 alleles demonstrate diminished current density and impaired channel trafficking, mirroring the hyperexcitability phenotype.

Conflicting Evidence: No studies to date have refuted the association between KCNQ2 variants and BFIE. Lack of additional evidence exceeding ClinGen scoring caps indicates a stable Moderate classification.

Conclusion: KCNQ2 loss-of-function variants in multiple BFIE families, supported by segregation and consistent functional deficits, establish a Moderate gene-disease relationship. Screening for KCNQ2 in infantile epilepsy panels informs clinical diagnosis and management, with M-channel openers such as retigabine offering potential targeted therapy.

Key Take-home: KCNQ2 haploinsufficiency underlies BFIE, with functional assays guiding personalized therapeutic strategies.

References

• Journal of human genetics • 2018 • Genetic analysis of benign familial epilepsies in the first year of life in a Chinese cohort. PMID:29215089
• Translational pediatrics • 2012 • Site-directed mutagenesis of neonatal convulsions associated KCNQ2 gene and its protein expression. PMID:26835270

Evidence Based Scoring (AI generated)