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 recessive developmental and epileptic encephalopathy (AR-DEE) (MONDO:0100062).
KCNQ3 was first reported in relation to AR-DEE in 2018 by Kothur et al. (PMID: 29852413) when a homozygous frameshift variant was detected in a male proband with familial neonatal seizures, hypotonia, and severe intellectual disability (ID). Subsequently in 2019, Lauritano et al. (PMID: 31440727) reported a different homozygous frameshift variant detected in a female proband with moderate intellectual disability (ID) and generalized convulsions associated with hypotonia, cyanosis, and clonic movements of the four limbs. Both probands were born to consanguineous parents. Of note, in PMID 29852413, patients in the same family reported clinical heterogeneity characterized by variable degrees of ID and the presentation of seizures.
In summary, KCNQ3 has limited association with autosomal recessive developmental and epileptic encephalopathy. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This was approved by the ClinGen Epilepsy GCEP on 8/1/2023 (SOP v.9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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