Pathogenic KCNQ3 variants are found throughout the gene. Nowadays we can often link a specific pathogenic variant to a specific KCNQ3-related disorder (i.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
KCNQ3 pathogenic variants exerting loss-of-function effects are associated with a spectrum of phenotypes ranging from self-limiting neonatal (familial) epilepsy (S(F)NE, MIM: 121201) and self-limiting infantile (familial) epilepsy (S(F)IE, MIM: 121201) to KCNQ3-developmental and epileptic encephalopathy (KCNQ3-DEE). Loss-of-function variants cause a decrease in potassium M-current, resulting in less suppression of repetitive neuronal firing. Carriership of one disease-causing loss-of-function variant results in S(F)NE or S(F)IE. In contrast, most KCNQ3-DEE is caused by two pathogenic variants exerting loss-of-function effects.
S(F)NE and S(F)IE are associated with missense (change of one base pair) variants distributed throughout the KCNQ3 gene. In contrast, KCNQ3-DEE is associated with a combination of two missense or frameshift (due to an insertion or deletion of base pairs) variants in the KCNQ3 gene.
Everyone has two copies of the KCNQ3 gene. Not all carriers of a single KCNQ3 loss-of-function variant present symptoms. S(F)NE and S(F)IE variants are mostly inherited from a healthy or mildly affected parent. The parent has a 50% chance of passing the abnormal variant to an offspring. If both parents carry a loss-of-function variant, there is a risk they both pass these to their offspring. This individual will have a more severe, KCNQ3-DEE phenotype.
Gain-of-function variants: channels are open more than is should be
Few KCNQ3 missense (change of one base pair) variants enhance channel function. Currently described gain-of-function variants are R230H, R230C, R230S, and R227Q, all located in the S4 voltage sensing domain of KCNQ3. These variants mostly are not inherited but occur de novo.
The international KCNQ3 database, RIKEE (Rational Intervention for KCNQ2/3 Epileptic Encephalopathy), can assist in variant interpretation (https://www.rikee.org/).