Pathogenic KCNQ2 variants are found throughout the gene. Genotype-phenotype correlations are striking, but caution must be taken since phenotypic variance exists even among carriers of the same variant.
Loss-of-function variants
KCNQ2 pathogenic variants exerting loss-of-function effects are associated with a spectrum of neonatal-onset phenotypes ranging from self-limiting familial epilepsy (S(F)NE, MIM:121200) to KCNQ2-developmental and epileptic encephalopathy (KCNQ2-DEE, MIM:613720). Loss-of-function variants cause a decrease in potassium M-current (IKM), resulting in less suppression of repetitive neuronal firing. A decrease of less than 50% of the IKM (haploinsufficiency) results in S(F)NE. In contrast, most KCNQ2-DEE pathogenic variants exert dominant-negative loss-of-function effects, and suppress the IKM by more than 50%.
S(F)NE is associated with a variety of heterozygous frameshift, stop-gain, intragenic and whole-gene deletions, splice variants, and missense variants distributed throughout the KCNQ2 gene. In contrast, KCNQ2-DEE is associated with, mostly de novo, missense and indels (in-frame deletions) variants. These variants can be found in four different functional hotspots (the S4 transmembrane segment, the pore, and the A-helix and B-helix in the C-terminus).
Gain-of-function variants
Few heterozygous KCNQ2 missense variants enhance channel function (gain-of-function) by causing a hyperpolarizing shift in voltage-dependent activation. Currently described gain-of-function variants are R198Q, R201C, R201H, R144W, R144Q, R144G, and V175L, all located in the voltage-sensing domain of KCNQ2. More gain-of-function variants are expected to be described.
The international KCNQ2 database, RIKEE (Rational Intervention for KCNQ2/3 Epileptic Encephalopathy), can assist in variant interpretation (https://www.rikee.org/).
Diagnostic testing
Diagnosis is most commonly made with genomic testing such as a gene panel or whole exome sequencing as phenotypic features of KCNQ2-related disorders overlap with those of other genetic etiologies.
KCNQ2