Molecular Characteristics

Pathogenic KCNQ3 variants are found throughout the gene. A limited number of pathogenic KCNQ3 variants are reported, complicating genotype-phenotype correlations. In addition, caution must be taken since phenotypic variance exists even among carriers of the same variant.

Loss-of-function variants
Heterozygous KCNQ3 complete loss is usually tolerated, as several truncating variants are present in gnomAD control database. Heterozygous disease-causing missense KCNQ3 variants are hypothesized to act through a mild dominant-negative effect, and are associated with a spectrum of early-onset epilepsy phenotypes ranging from self-limiting neonatal (familial) epilepsy (S(F)NE, MIM: 121201) and self-limiting infantile (familial) epilepsy (S(F)IE, MIM: 121201).
In contrast, KCNQ3-DEE is caused by homozygous or compound heterozygous pathogenic variants exerting severe loss-of-function effects.
Loss-of-function or dominant negative variants cause a decrease in potassium M-current (IKM), resulting in less suppression of repetitive neuronal firing.

Gain-of-function variants
Few heterozygous KCNQ3 missense variants enhance channel function (gain-of-function) by causing a hyperpolarizing shift in voltage-dependent activation. Currently described gain-of-function variants are R230H, R230C, R230S, and R227Q, all located in the S4 voltage-sensing domain of KCNQ3.

The international KCNQ2/3 database, RIKEE (Rational Intervention for KCNQ2/3 Epileptic Encephalopathy), can assist in variant interpretation (https://www.rikee.org/).

Diagnostic testing
Diagnosis is most made with genomic testing such as a gene panel or whole exome sequencing as phenotypic features of KCNQ3-related disorders overlap with those of other genetic etiologies.