Variants in FOXC1 and FOXC2 identified in patients with conotruncal heart defects

Conotruncal heart defects (CTD), subtypes of congenital heart disease, result from abnormal cardiac outflow tract development (OFT). FOXC1 and FOXC2 are closely related members of the forkhead transcription factor family and play essential roles in the development of OFT. We confirmed their expression pattern in mouse and human embryos, identifying four variants in FOXC1 and three in FOXC2 by screening these two genes in 605 patients with sporadic CTD. Western blot demonstrated expression levels, while Dual-luciferase reporter assay revealed affected transcriptional abilities for TBX1 enhancer in two FOXC1 variants and three FOXC2 variants. This might result from the altered DNA-binding abilities of mutant proteins. These results indicate that functionally impaired FOXC1 and FOXC2 variants may contribute to the occurrence of CTD. •FOXC1/2 expressin the OFT at early embryonic stages.•Several nonsynonymous and loss-of-function FOXC variants were identified in conotruncal heart defect patients.•FOXC variants can affect transcriptional abilities for TBX1 enhancer and alter DNA-binding abilities of mutant proteins.