Congenital heart diseases (CHDs) affect nearly 1% of all neonates and show an increasing tendency. The complex inheritance patterns and multifactorial etiologies make these defects difficult to be identified before complete manifestation. Genetic screening has identified hundreds of specific mutant sites for CHDs based on cardiac transcriptional factors. GATA4 is a master regulator required for ventral morphogenesis and heart tube formation. Its mutation is most widely studied in CHDs. In the past decades, over 100 GATA4 mutant sites have been reported, but only a few functional sites have been identified. Thus, it is important to distinguish deleterious sites from neutral sites. In silico prediction of functional sites using bioinformatics tools can provide the valuable information, but it is not solid enough. Here, the roles of GATA4 in heart development is discussed in detail and its mutation sites in protein coding region are summarized systematically, providing an integrated resource for GATA4 mutations. Furthermore, we discussed the advantage and disadvantage of different methods for functional mutation identification. Especially, the disease model of induced pluripotent stem cell is emerging as a powerful tool to assess GATA4 mutations in human. In the recent years, single-cell based high-throughput sequencing is being applied in preimplantation diagnosis and assisted reproduction progressively, providing a new strategy for the prevention of congenital diseases as we discussed. Based on functional mutant sites identification, preimplantation diagnosis will contribute to CHDs prevention eventually.
Keywords: Cardiomyocyte; Disease model; Gene editing; Genetic diseases prevention; Induced pluripotent stem cell.
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