FOXA2 was first reported in relation to autosomal dominant combined pituitary hormone deficiencies in 2017 (Giri et al., PMID: 28973288). Probands with this condition present with various types of structural congenital heart disease, including patent ductus arteriosus, and double outlet right ventricle. Six variants (5 missense, 1 nonsense) that have been reported in six probands in five publications (PMIDs: 28973288, 29329447, 30414530, 33729509, 31294511) are included in this curation. Variants were reported to be de novo for all cases in which parents were available for testing; for two of the missense variants, supporting evidence for reduced function is available (PMIDs: 28973288, 29329447). Thus far, reported missense variants appear to cluster in or near the forkhead domain, which may affect the DNA binding ability of this transcriptional activator (PMID: 33729509). At least two probands with a similar phenotype and de novo deletions encompassing FOXA2 have been reported, but were not scored in this curation (PMIDs: 31294511, 32277595). Therefore, the mechanism of pathogenicity appears to be LOF leading to haploinsufficiency. This gene-disease association is also supported by expression studies in both mouse and human embryos (PMID: 28973288). In summary, there is moderate evidence to support the relationship between FOXA2 and autosomal dominant combined pituitary hormone deficiencies. This classification was approved by the ClinGen Brain Malformations gene curation expert panel on November 22, 2022 (SOP 9), and the Congenital Heart Disease Gene Curation Expert Panel on October 8, 2025 (SOP 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).
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