KCNQ2 – Developmental and Epileptic Encephalopathy 7

KCNQ2 encodes the voltage-gated potassium channel KV7.2, critical for neuronal M-currents that regulate excitability. Heterozygous de novo variants in KCNQ2 cause developmental and epileptic encephalopathy 7, characterized by neonatal onset pharmacoresistant seizures, profound developmental delay, and distinctive EEG patterns.

Clinical Validity

The association between KCNQ2 and developmental and epileptic encephalopathy 7 is classified as Strong based on 9 unrelated de novo probands with supportive functional data, consistent segregation, and experimental concordance.

Genetic Evidence

Nine unrelated infants harboring de novo KCNQ2 missense variants presented with neonatal-onset refractory seizures and developmental impairment:

• c.545T>G (p.Val182Gly) in a neonate with unique inter- and postictal focal rhythmic theta waves ([PMID:28832002]).
• c.794C>T (p.Ala265Val) in a case complicated by ventricular tachycardia ([PMID:32362866]).
• Seven additional de novo missense variants across pore and voltage-sensor domains in independent severe encephalopathy cohorts ([PMID:24318194]).

Functional Evidence

Heterologous expression in Xenopus oocytes and mammalian cells demonstrates that many KCNQ2 encephalopathy variants exert dominant-negative or gain-of-function effects, reducing or altering M-current density and gating:

• Dominant-negative suppression of wild-type KV7.2/KV7.3 currents and depolarizing activation shifts ([PMID:24318194]).
• Mislocalization of heteromeric channels and moderate current reduction for p.Ala294Val, without dominant-negative effect ([PMID:26007637]).

Mechanism of Pathogenicity

These findings support a mechanism of altered channel function—either dominant-negative loss-of-function or gain-of-function gating shifts—leading to neuronal hyperexcitability and network dysfunction in developmental and epileptic encephalopathy 7.

Conflicting Evidence

No conflicting or refuting studies have been reported specific to developmental and epileptic encephalopathy 7 in KCNQ2.

Conclusion

The strong genetic and moderate experimental evidence establish KCNQ2 as a key gene for developmental and epileptic encephalopathy 7. Early genetic diagnosis enables precision management, including trial of channel modulators.

Key Take-home: De novo KCNQ2 variants cause a severe neonatal-onset encephalopathy via altered M-current function, with direct implications for targeted therapy.

References

• Epileptic disorders • 2017 • Pointed rhythmic theta waves: a unique EEG pattern in KCNQ2-related neonatal epileptic encephalopathy. PMID:28832002
• Frontiers in neurology • 2020 • KCNQ2-Neonatal Epileptic Encephalopathy Complicated by Ventricular Tachycardia: A Case Report. PMID:32362866
• Annals of neurology • 2014 • Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. PMID:24318194
• Neurobiology of disease • 2015 • A recurrent KCNQ2 pore mutation causing early onset epileptic encephalopathy has a moderate effect on M current but alters subcellular localization of Kv7 channels. PMID:26007637

Evidence Based Scoring (AI generated)

Gene–Disease Association Strong 9 unrelated de novo probands with severe neonatal-onset epileptic encephalopathy and concordant functional studies Genetic Evidence Strong 9 de novo pathogenic missense variants identified in unrelated probands (1 in Val182Gly [PMID:28832002]; 1 in Ala265Val [PMID:32362866]; 7 in diverse residues [PMID:24318194]) Functional Evidence Moderate Multiple functional assays demonstrate dominant-negative or gain-of-function effects on M-current density and gating in heterologous systems [PMID:24318194; PMID:26007637]