Pathogenic KCNQ2 variants are found throughout the gene. Nowadays we can often link a specific pathogenic variant to a specific KCNQ2-related disorder (f.e. with or without developmental delay), but caution must be taken since interindividual variance exists.
Loss-of-function variants: channels are closed more than is should be
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) to KCNQ2-developmental and epileptic encephalopathy (KCNQ2-DEE). Loss-of-function variants cause a decrease in potassium M-current (IKM), resulting in less suppression of neuronal firing. A decrease of less than 50% of the IKM results in S(F)NE. In contrast, most KCNQ2-DEE pathogenic variants suppress the IKM by more than 50%.
S(F)NE is associated with a variety of pathogenic variants distributed throughout the KCNQ2 gene. In contrast, KCNQ2-DEE is only associated with missense (change of one base pair) and indels (deletion of one amino-acid) variants. These variants can be found in four different locations of the KCNQ2 gene, called the functional hotspots (the S4 transmembrane segment, the pore, and the A-helix and B-helix in the C-terminus).
S(F)NE variants are mostly inherited from a parent. Since everyone has two copies of the KCNQ2 gene, the parent has a 50% chance of passing the abnormal variant to an offspring. KCNQ2-DEE variants mostly arise spontaneously and or not inherited from a parent (de novo). Sometimes an unaffected or mildly affected parent carries the KCNQ2-DEE variant in only a few cells of his/her body. This is called mosaicism. If the variant is present in (a few) germ cells, the parent can pass the variant to an offspring who can be more severely affected. The risk of passing this variant lies between 0% (variant is not present in germ cells) and 50% (variant is present in all gem cells).
Gain-of-function variants: channels are open more than is should be
Few KCNQ2 missense (change of one base pair) variants enhance channel function. 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/).
KCNQ2