YY1 was first reported in relation to autosomal dominant complex neurodevelopmental disorder (also called Gabriele de Vries syndrome (GADVS)) in 2017 (Gabriele et al., PMID: 28575647). Phenotypic features reported in affected individuals include variable intellectual disability (ID), various neurological disorders (hypotonia, abnormal movements, behavioral disorders, brain abnormalities), feeding difficulties, ophthalmological abnormalities, significant but not specific facial features, and more rarely cardiac or renal malformations.
Twenty-nine variants (missense variants in the YY1 zinc finger or nonsense and frameshift variants) have been reported in 29 probands in 11 publications (including PMIDs: 28575647, 32627382, 35027293, 39987231, and others documented in the genetic evidence) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function that leads to reduced DNA binding, widespread transcriptional downregulation and abnormal gene methylation (PMID: 28575647).
This gene-disease relationship is also supported by experimental evidence of distinct DNA methylation signatures in patients with YY1 pathogenic mutations (PMID: 350207293) and impaired transcriptional regulation in patient-derived induced pluripotent stem cells (PMID: 39987231). In addition to widespread transcriptional downregulation, brain organoids from patient-derived iPS cells showed impaired formation of ventricle-like structures in early stages of cortical development (PMID: 39987231).
In summary, there is definitive evidence to support the gene-disease relationship between YY1 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 was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 1, 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.