Submission Details

KCNQ3 encodes the potassium voltage-gated channel, KQT-like subfamily, member 3, which is expressed in the brain and regulates the resting membrane potential and sets the threshold and duration of the action potential in excitable cells (PMID: 33013448). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have found differences in molecular mechanism, inheritance pattern, and phenotypic variability for this gene. Therefore, this curation has been split into multiple entities: autosomal dominant self-limited familial neonatal epilepsy (MONDO:0100023; thought to be loss of function), autosomal dominant complex neurodevelopmental disorder (MONDO:0100038; thought to be gain of function), and autosomal recessive developmental and epileptic encephalopathy (MONDO:0100062, mechanism unclear). These split curations have been curated separately by the Epilepsy GCEP and this entry will only cover autosomal dominant self-limited familial neonatal epilepsy (SLFNE) (MONDO:0100023).

KCNQ3 was first reported in relation to SLFNE in 1998 (Charlier et al., PMID:9425900) when a missense variant was found in 13 affected individuals in the same family. The mechanism of pathogenicity involves loss-of-function missense variants, mainly inherited from symptomatic parents. This mechanism has been confirmed with a multitude of functional studies, most using a Xenopus laevis expression system and voltage clamp techniques to discover a reduced expression or impaired function of the potassium channel when a variant is present (PMID: 25524373, 27781029, 9872318, 18625963, 14534157, 33013448).

Fifteen missense variants reported in 18 probands across 16 publications (PMIDs: 9425900, 10852552, 14534157, 18249525, 18625963, 23146207, 24375629, 25052858, 25278462, 25524373, 27781029, 27888506, 31302675, 33013448, 34153113, 35384780) were scored in this curation. Of note, case 15 in Sands et al. (PMID:27888506) has a deletion of exons 1-15; because this paper did not provide specific breakpoints, it cannot be formally entered into this curation. However, we have awarded this predicted/proven null variant 1.5 points. Bringing the total genetic evidence, including case level segregation, to 9.4 points. This gene-disease relationship is supported by two papers discussing functional alteration in non-patient cells (PMID: 35857840, 18425618) and an additional paper outlining the protein interactions of KCNQ3 and KCNQ2 (PMID: 9677360). In this curation, experimental evidence was awarded 1.5 points.

In summary, KCNQ3 has a moderate association to autosomal dominant self-limited familial neonatal epilepsy (SLFNE).The total number of points for this curation is 9.4 plus 1.5 pts for the multi-exon deletion, bringing our total to 10.9 points.This curation was approved by the ClinGen Epilepsy GCEP on 8/1/2023 (SOP v.9).