GATA6 was first reported in relation to autosomal dominant GATA6- related congenital heart disease with or without pancreatic agenesis or neonatal diabetes in 2009 (Kodo et al. 2009, PMID: 19666519). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms, inheritance pattern and phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity: Atrial septal defect 9, Conotruncal heart malformations, Tetralogy of Fallot, Ventricular septal defect, Atrioventricular septal defect, Bicuspid aortic valve, Transposition of the great arteries, Persistent truncus arteriosus, Congenital heart disease with pancreatic agenesis, and Congenital heart disease with neonatal diabetes. At least ten unique variants (missense, nonsense, frameshift) that have been reported in ten probands in seven publications (PMIDs: 19666519, 23020118, 25937001, 28049534, 29653232, 31301121, 35595280) are included in this curation. Four of the ten variants were de novo occurrences. Variants in GATA6 co-segregated in at least 4 members in a family with bicuspid aortic valve (PMID: 29653232). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is supported by biochemical function study, functional alteration data, and protein interaction data (PMIDs: 10330176, 32442395, 36525927, 10330176). Experimental evidence also includes a mouse model with conditional deletion of GATA6 that recapitulated the CHD phenotype (PMID: 16557299), a hIPSC cell culture model showing the importance of GATA6 in development of the heart, endodermal lineages, pancreas, and diaphragm (PMID: 33054971), and rescue in a zebrafish GATA6 knockout mutant line (PMID: 36525927). In summary, GATA6 is definitively associated with autosomal dominant GATA6- related congenital heart disease with or without pancreatic agenesis or neonatal diabetes. 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 Congenital Heart Disease GCEP on the meeting date 11/21/2023 (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).
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