Upregulation of TBX1 by genetic variants are associated with human congenital heart disease

Congenital heart disease (CHD) is the most common human birth defect worldwide and also an important cause of childhood morbidity and mortality. The transcription factor of TBX1 early expressed in embryonic cardiac progenitor cells underlys embryo cardiogenesis in a dosage-dependent manner. Imbalanced TBX1 level has been shown to lead to cardiac defects. To study the association of TBX1 genetic variants with CHD susceptibility, we screened genetic variants in 409 CHD patients and 203 healthy controls. One single nucleotide polymorphism (SNP), rs41260844, in TBX1 promotor region was identified to be associated with CHD. Functional studies showed the minor allele of rs41260844 is associated with higher CHD risk and increases TBX1 promoter activity through attenuating TBX1 promoter binding affinity with nuclear protein(s). In addition, a novel case-specific missense rare mutation of p.P164L in TBX1 T-box domain was identified and predicted as deleterious mutation, which showed a trend of increased protein function. In summary, we concluded that a higher TBX1 expression level or activity is associated with CHD susceptibility, which could affect TBX1 downstream targets and thus disrupt the balance of the complex regulation network during cardiogenesis. This study deepens our current understanding of embryo cardiogenesis and CHD etiology.