CYFIP2 was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2018 (Nakashima et al., PMID: 29534297). The phenotypes of CYFIP2-related complex neurodevelopmental disorder vary from developmental epileptic encephalopathy with severe epilepsy, profound intellectual disability and hypotonia to mild or moderate intellectual disability without seizures. Twenty heterozygous missense variants reported in twenty-eight probands in three publications are included in this curation (PMID: 29534297, 30664714, 33149277). Variants found in most individuals with CYFIP2-related complex neurodevelopmental disorder are of de novo origin. Of the 28 probands, 13 carried hotspot variants at arginine 87 and had developmental epileptic encephalopathy phenotypes.
Functional studies of several missense variants including the recurrent p.Arg87Cys variant showed gain-of-function effects (PMID: 29534297, 32486060). While four cases of putative loss-of-function variants have been reported, the Epilepsy GCEP decided not to include these cases in the curation because the role of loss-of-function variants as a disease mechanism is unclear at this time. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.
In summary, there is definitive evidence supporting the relationship between CYFIP2 and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification has been approved by ClinGen Epilepsy GCEP on the meeting date, May 6, 2025 (SOP version 11).
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.