KCNC2 was first reported in relation to developmental and epileptic encephalopathy in 2020 (Vetri L, et al, PMID: 31972370). Affected individuals present with seizures (varying types) in the first year of life, global developmental delay / intellectual disability, hypotonia, ataxia, and behavioral abnormalities. Fourteen variants (heterozygous missense) that have been reported in 14 probands in 6 publications (PMIDs: 31972370, 35314505, 35366058, 36090251, 36087422, 36035247) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be both gain and loss of function. One reported variant is suspected to have a dominant negative effect (PMID: 35314505).
In addition to case-level evidence, the gene-disease relationship is supported by in vitro cell culture functional assays. (PMIDs: 35314505, 36090251, 36087422, 36035247). Depending on the variant, modified KCNC2 channels showed both gain-of-function (a shift towards a hyperpolarized state with increased time to deactivation) and loss-of-function (reduced total current amplitude). A KCNC2 knockout mouse model has also been published, however it was not scored given that the KCNC2 variants seen in humans have been missense rather than truncating (PMID:11124984).
In summary, there is definitive evidence supporting the relationship between KCNC2 and autosomal dominant 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 Intellectual Disability and Autism GCEP on the meeting date December 14, 2023 (SOP Version 10).
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