KCNQ2 was first reported in a proband with autosomal dominant neonatal encephalopathy with nonepileptic myoclonus 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, attributed primarily to p.R230C/H/S, p.R198Q, and p.R144Q/W/G recurrent de novo variants), and neonatal encephalopathy with non-epileptic myoclonus (MONDO:0100456; thought to be gain of function, attributed to p.R201C, p.R201H, and p.V175L recurrent de novo variants). The split curations have been curated separately by the Epilepsy GCEP and this entry will only cover autosomal dominant neonatal encephalopathy with nonepileptic myoclonus (MONDO:0100456).
Three recurrent de novo missense variants, p.R201C, p.R201H, and p.V175L, reported in 12 probands in three publications, are included in this curation (PMIDs: 28139826, 23692823, 25092550). Patients often present with exaggerated startle responses and/or myoclonus within the first days or weeks or life, along with encephalopathy and hypotonia from birth (PMID: 28139826). Patients also commonly have respiratory insufficiency, central hypoventilation, a persistent suppression burst pattern of EEG background, and recurrent bouts of myoclonus that are not accompanied by epileptic discharges on electroencephalography (PMID: 28139826). Evolution to pharmacoresistant seizures is common, as is continued profound global developmental delay. The mechanism of pathogenicity is thought to be gain of function (PMIDs: 25740509, 27030113). In summary, there is a definitive relationship between KCNQ2 and autosomal dominant neonatal encephalopathy with nonepileptic myoclonus. 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 February 15, 2022 (SOP Version 8).
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).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.