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 autosomal recessive DEE resulting from biallelic variants in DNM1.
Four variants (nonsense, frameshift) that have been reported in four patients are included in this curation (PMIDs: 36553519, 34172529, 37900685). Of note, all variants were found to be in the homozygous state and consanguinity was noted. Most probands experienced symptom onset within the first year of life and presented with a variety of seizure types, including tonic and myoclonic. Brain imaging findings include volume loss and thinning of the corpus callosum. The mechanism of pathogenicity appears to be loss of function.
In summary, there is moderate evidence to support the relationship between DNM1 and autosomal recessive DEE. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on the meeting date February 6, 2024 (SOP Version 10).
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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