FOXC2 was first reported in relation to autosomal dominant lymphedema-distichiasis syndrome in 2000 (Fang et al., PMID: 11078474). This condition involves primary lymphedema of the lower extremities and distichiasis to various degrees. Prenatal features may include congenital heart disease, cleft palate, cystic hygroma, and nonimmune fetal hydrops. Twenty-one variants (nonsense, frameshift, and missense) that have been reported in at least 21 probands in nine publications (PMIDs: 11078474, 19394045, 21918810, 25252123, 29906362, 31974414, 20450314, 22349027, 11371511) 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. This gene-disease relationship is also supported by animal models, expression studies, and in vitro functional assays (PMIDs: 12719382, 15322537, 27214551, 26389677, 15465483, 19398761). Foxc2 heterozygous knockout mouse models demonstrate a postnatal lymphatic and eyelash phenotype as well as dermal lymphatic hyperplasia, and a conditional Foxc2 knockout mouse model was shown to recapitulate the human lymphatic phenotype. In summary, there is definitive evidence supporting the relationship between FOXC2 and autosomal dominant lymphedema-distichiasis 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 Prenatal GCEP on the meeting date September 26, 2023 (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.