HEY2 was first reported in relation to autosomal dominant congenital heart disease in 2020 (Edwards et al., PMID: 32368696). 9 variants (missense, nonsense, frameshift, in-frame deletion) that have been reported in at least 12 probands in 2 publications (PMIDs: 32820247, 32368696) are included in this curation. The gene shows a dosage effect, with mostly heterozygous cases reported, although there is a family with three homozygotes severely affected and heterozygous individuals with a milder phenotype. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (NCBI fetal expression data, interaction evidence; PMID: 16199874 ). HEY2 is shown to inhibit GATA4 and *GATA6 *expression and function. GATA4 has been classified as definitive for autosomal dominant structural congenital heart disease. *GATA6 *has been classified as definitive for autosomal dominant congenital heart disease with or without pancreatic agenesis or neonatal diabetes. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 7/2/2024 (SOP Version 10).
HEY2 was first reported in relation to autosomal dominant congenital heart disease in 2020 (Edwards et al., PMID: 32368696). 9 variants (missense, nonsense, frameshift, in-frame deletion) that have been reported in at least 12 probands in 2 publications (PMIDs: 32820247, 32368696) are included in this curation. The gene shows a dosage effect, with mostly heterozygous cases reported, although there is a family with three homozygotes severely affected and heterozygous individuals with a milder phenotype. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (NCBI fetal expression data, interaction evidence; PMID: 16199874 ). HEY2 is shown to inhibit GATA4 and GATA6 expression and function. GATA4 has been classified as definitive for autosomal dominant structural congenital heart disease. GATA6 has been classified as definitive for autosomal dominant congenital heart disease with or without pancreatic agenesis or neonatal diabetes. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 7/2/2024 (SOP Version 10).
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