RNF168 was first reported in relation to autosomal recessive RIDDLE syndrome in 2009 (Stewart et al., PMID: 19203578). RIDDLE syndrome is named for its clinical features which include Radiosensitivity, ImmunoDeficiency, Dysmorphic features, and LEarning difficulties. Four variants (nonsense and frameshift) that have been reported in 3 probands in 3 publications are included in this curation (PMIDs: 19203578, 21394101, 29255463). Information regarding the phenotype of heterozygous carriers is limited; however, one parent of a proband was noted to have B cell chronic lymphocytic leukemia (PMID: 19203578). The mechanism of pathogenicity is loss of function.
This gene-disease association is supported by biochemical studies, functional and rescue assays, and an animal model (PMIDs: 19203578, 17940005, 29255463, 21394101, 21552324). RNF168 is critical for double stranded break repair (PMID: 19203578), and RIDDLE syndrome patient cells show defects in 53BP1-mediated DNA damage signaling (PMID: 17940005, 29255463). These defects are rescued by wild type RNF168 (PMID: 19203578, 21394101). RNF168 knockout mice have radiosensitivity and immunodeficiency consistent with RIDDLE syndrome (PMID: 21552324).
In summary, RNF168 is definitively associated with autosomal recessive RIDDLE syndrome. 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 SCID/CID GCEP on the meeting date July 21, 2022 (SOP Version 9).
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.