Individuals with monoallelic variants in the RANBP2 gene and features of acute necrotizing encephalopathy (ANE) were first reported in the literature in 2009 (Neilson et al., PMID:19118815). ANE is characterized by a variable presentation of encephalopathy, seizures and potential coma shortly after infection in otherwise healthy and cognitively typical individuals. ANE is also notable for characteristic MRI findings of polyfocal lesions in the thalami, pons and brainstem. Of note, there have been additional individuals reported with RANBP2 variants in large autism cohorts (PMIDs: 35982160, 28714951). Due to limited phenotypic information about these individuals, we are opting not to include them in this curation for ANE.
In multiple reports of patients with ANE and variants in RANBP2, a recurrent p.Thr585Met (c.1880C>T) variant is present. This variant has been identified as de novo in some individuals with ANE and has also been identified to segregate with disease in some families (PMIDs: 19118815, 19811512, 20570537, 21945312, 26110162, 34377735). Although typically found in the heterozygous state, at least one publication identifies an individual with disease who carries this variant in the homozygous state (PMID: 36029610). Other missense variants are present in individuals with disease, but with limited additional evidence (PMID:19118815, 20473521, 25170550). No experimental data supporting a relationship between RANBP2 and ANE has been included in this curation. Of note, given the low penetrance associated with this condition, additional supporting data is needed to further establish a conclusive gene-disease relationship.
In summary, there is moderate evidence to support the relationship between RANBP2 and acute necrotizing encephalopathy. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date April 2, 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).
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.