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 complex neurodevelopmental disorder (CND) (MONDO:0100038).
KCNQ3 was first reported in relation to CND in 2012 by Rauch et al. (PMID:23020937) when a missense variant was found in a proband with severe intellectual disability and multifocal epileptic activity. The mechanism of pathogenicity involves gain-of-function missense variants, usually occurring de novo (PMIDs: 31177578, 25740509). Eight missense variants reported in 24 probands across 7 publications (PMIDs: 23020937, 28135719, 31177578, 31238879, 33004838, 33037390, 34356170) were scored in this curation. Several recurrent variants have been identified: four probands carried the variant p.Arg227Gln and three different recurrent amino acid substitutions have been reported in 15 probands for p.Arg230 (p.Arg230Cys, p.Arg230His, p. Arg230Ser).
In summary, KCNQ3 is definitely associated with autosomal dominant complex neurodevelopmental disorder. This was approved by the ClinGen Epilepsy GCEP on 8/1/2023 (SOP v.9).
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