TBX20 loss-of-function mutation contributes to double outlet right ventricle.

Congenital heart disease (CHD), the most prevalent birth defect in humans worldwide, is still a leading non‑infectious cause of infant morbidity and mortality. Increasing evidence demonstrates that genetic risk factors play a key role in the pathogenesis of CHD, and more than 50 genes have been linked to various types of CHD. Nevertheless, CHD is a heterogeneous disorder and the genetic components underpinning CHD in an overwhelming majority of cases remain unknown. In the present study, the entire coding exons and flanking introns of the TBX20 gene, which codes for a T-box transcription factor essential for the proper development of the heart, were sequenced in a cohort of 146 unrelated patients with CHD. The available relatives of the index patient harboring an identified mutation and 200 unrelated ethnically matched healthy individuals used as the controls were also genotyped for TBX20. The functional characteristics of the TBX20 mutation were assayed by using a dual-luciferase reporter assay system. As a result, a novel heterozygous TBX20 mutation, p.R143W, was identified in an index patient with double outlet right ventricle (DORV). Genetic analyses of the pedigree of the proband revealed that in the family, the mutation co-segregated with DORV transmitted in an autosomal dominant pattern with complete penetrance. The missense mutation was absent in 400 control chromosomes and the altered amino acid was completely conserved evolutionarily across species. Functional analysis revealed that mutant TBX20 had a significantly diminished transcriptional activity compared with its wild-type counterpart. To the best of our knowledge, this study is the first to report the association of TBX20 loss-of-function mutation with increased susceptibility to DORV in humans, which provides novel insight into the molecular mechanisms responsible for CHD, suggesting potential implications for the antenatal prophylaxis of CHD.