KCNQ2 was first reported in relation to autosomal dominant neonatal-onset developmental and epileptic encephalopathy in 2012 (Weckhuysen et al., PMID: 22275249). Assertions have been made for a relationship between KCNQ2 and several neurodevelopmental presentations. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have found differences in molecular mechanism and phenotypic variability between these assertions. Therefore, the curation has been split into multiple autosomal dominant disease entities: neonatal-onset developmental and epileptic encephalopathy (MONDO:0100455; thought to be dominant negative), self-limited familial neonatal epilepsy (MONDO:0100023; thought to be loss of function), complex neurodevelopmental disorder (MONDO:0100038; thought to be gain of function), and neonatal encephalopathy with non-epileptic myoclonus (MONDO:0100456; thought to be gain of function). The split curations have been curated separately by the Epilepsy GCEP and this entry will only cover autosomal dominant neonatal-onset developmental and epileptic encephalopathy (MONDO:0100455).
Twenty-two missense variants that have been reported in 29 probands in three publications are included in this curation (PMIDs: 22275249, 24107868, 23621294). Probands display multiple features, including seizure onset as early as the first day of life and neurodevelopmental delays that range from moderate to severe. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is thought to be dominant negative (PMID: 24318194). This gene-disease relationship is also supported by animal models and functional alteration studies (PMIDs: 23440208, 24318194, 34911751). In summary, there is a definitive relationship between KCNQ2 and autosomal dominant neonatal-onset developmental and epileptic encephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on June 21, 2022 (SOP Version 9).
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