Targeted sequencing identifies novel GATA6 variants in a large cohort of patients with conotruncal heart defects

Abstract Studies have highlighted the critical role of GATA6 in conotruncal heart defects (CTDs). Nevertheless, relationship between GATA6 variants and different CTDs remains largely unknown. Here GATA6 gene was screened in 542 patients with CTDs using targeted sequencing. Variant frequency was 2.0% (11/542). Three novel variants: c.86C > A (p.A29E), c.296T > A (p.V99D) and c.1254delC (p.S418fs) were identified in patients with transposition of the great arteries, double outlet right ventricle and persistent truncus arteriosus, respectively, but in none of the 400 controls. Western blot revealed that A29E and V99D mutant protein had similar expression pattern with wild-type GATA6 protein, but S418fs mutant protein appeared as a truncated doublet. Reporter gene assay demonstrated that A29E and V99D mutant protein retained the ability to activate BNP and ANF promoter, whereas S418fs mutant protein failed to transactivate both of them, compared with wild-type. Subcellular localization of wild-type, A29E and V99D mutant protein were in the nucleus, while S418fs mutant protein was expressed both in the nucleus and cytoplasm. In conclusion, GATA6 variant frequency in sporadic CTDs patients was higher than that in other congenital heart diseases. Variant c.1254delC was a pathogenic variant associated with CTDs, especially PTA, whereas c.86C > A and c.296T > A should be considered as likely pathogenic variants.