The CASK gene, which encodes a synaptic scaffolding protein, has been associated with X-linked syndromic intellectual disability using the ClinGen Clinical Validity Framework as of 7/3/2019. This association was made using both case-level genetic evidence, as well as experimental data. It should be noted that there are additional cases available in the literature, however, the four publications presented here surpass the cut-off for genetic evidence. Some cases could not be scored on the GCI due to variants extending larger than 10kb (see Moog et al., 2011 (PMID: 21954287) and Moog et al., 2015 (PMID: 25886057)). The large number of cases with variants in ClinVar or the ClinGen Allele Registry allowed for scoring cut-offs to be reached, even without including these cases. This association is supported by mouse models that recapitulate the phenotype expressed in humans, though relatively few CASK animal models have been studied. In summary, CASK is definitively associated with X-linked syndromic intellectual disability.
CASK, which encodes a synaptic scaffolding protein, was first reported in relation to X-linked syndromic intellectual disability in 2008 (Najm et al., PMID: 19165920). Sixteen variants (nonsense, splice, frameshift, start loss, missense) that have been reported in 18 probands in four publications (PMIDs: 19165920, 21735175, 21954287, 25886057) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Some cases could not be scored because the deletions were larger than 10 kb (see Moog et al., 2011, PMID: 21954287, and Moog et al., 2015, PMID: 25886057). This gene-disease relationship is also supported by mouse models that recapitulate the phenotype in humans.
In summary, there is definitive evidence supporting the relationship between CASK and X-linked syndromic intellectual disability. 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 Intellectual Disability and Autism Gene Curation Expert Panel on July 9, 2019 (SOP Version 6).
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.