HEY1 was first reported in relation to autosomal dominant congenital heart disease in 2016 (Sicko et al., PMID: 27788187). Three individuals with CHD were identified with CNVs (2 gross duplications and 1 gross deletion), however these CNVs encompass multiple genes near the transcriptional repressor HEY1, and thus were not scored (PMID: 27788187). A missense variant was reported in 2 individuals of a family with CHD, however functional assay showed no effect of the variant on transcriptional activity (PMID: 35737725). This gene-disease relationship is supported by evidence of Hey1 expression exclusively in the atria of the embryonic mouse heart and protein interaction studies with GATA proteins (PMIDs: 10415358, 15485867). No apparent heart defects were observed in the Hey1 knockout mouse but was seen in two double knockout mouse models (Hey1/2 and Hey1/L) suggesting that the Hey proteins play partially redundant roles during cardiac development (PMIDs: 15107403, 17303760). In summary, the evidence supporting the relationship between HEY1 and autosomal dominant congenital heart disease has been disputed, and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role HEY1 plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date August 6th, 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.