DNM1 was first reported in relation to autosomal dominant developmental and epileptic encephalopathy (DEE) in 2014 (EuroEPINOMICS-RES Consortium et al., PMID:25262651). Since this initial report, patients with DEE and biallelic variants in DNM1 have also been identified (PMIDs: 36553519, 34172529, 37900685). DEE patients with biallelic DNM1 variants typically have putative loss of function variants (nonsense, frameshift), whereas almost all individuals with monoallelic DNM1 variants have de novo missense variants. Due to these differences in variant type and inheritance pattern, we have chosen to split these individuals into two separate curations: one for autosomal dominant DEE and the other for autosomal recessive DEE. This curation focuses solely on individuals with DEE resulting from monoallelic variants in DNM1.
Eighteen variants (missense, in-frame insertion) that have been reported in 25 patients are included in this curation (PMIDs: 25262651, 26611353, 26648591, 26795593, 34386584, 29397573, 29588952, 29427836, 31920647, 28667181). For all individuals with parental samples available, their variants have been confirmed to occur de novo. Of note, six individuals documented in this curation were found to have the recurrent de novo variant p.Ala237Trp. The mechanism of disease appears to be dominant negative (PMIDs: 28667181, 37132416). In summary, there is definitive evidence supporting the relationship between autosomal dominant developmental and epileptic encephalopathy and DNM1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
This classification was originally approved by the ClinGen Epilepsy GCEP on December 13, 2016. It was subsequently updated in September 2021 to change the disease term from early infantile epileptic encephalopathy to developmental and epileptic encephalopathy, but no new evidence was evaluated and the final classification was not changed. On February 6, 2024, due to new reports of autosomal recessive disease, this curation underwent administrative updates to include lumping and splitting information in the evidence summary. Additionally, scoring of case-level data was updated to be consistent with SOP Version 10; to retain the final classification of Definitive, new case-level data was included in this curation.
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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