The ventriculoseptal defect (VSD) is the most common form of congenital heart disease and a leading noninfectious cause of infant mortality. Growing evidence demonstrates that genetic defects are associated with congenital VSD. Nevertheless, VSD is genetically heterogeneous, and the molecular basis for VSD in an overwhelming majority of patients remains unknown. In this study, the whole coding region of GATA5, a gene encoding a zinc finger transcription factor crucial for normal cardiogenesis, was sequenced in 120 unrelated patients with VSD. The available relatives of the patient harboring the identified mutation and 200 unrelated individuals used as controls were subsequently genotyped. The causative potential of a sequence variation was evaluated by MutationTaster, and the functional effect of the mutation was characterized using a luciferase reporter assay system. As a result, a novel heterozygous GATA5 mutation, p.L199V, was identified in a patient with VSD, which was absent in 400 control chromosomes. Genetic analysis of the mutation carrier's available family members showed that the substitution co-segregated with VSD transmitted in an autosomal dominant pattern. The p.L199V variation was automatically predicted to be disease causing, and the functional analysis showed that the GATA5 p.L199V mutant protein was associated with significantly reduced transcriptional activation compared with its wild-type counterpart. To the best of the authors' knowledge, this is the first report on the link of functionally compromised GATA5 to human VSD, suggesting potential implications for the early prophylaxis and personalized treatment of VSD.
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.
Congenital heart disease (CHD) is the most prevalent type of birth defect in humans and is the leading non-infectious cause of infant death worldwide. There is a growing body of evidence demonstrating that genetic defects play an important role in the pathogenesis of CHD. However, CHD is a genetically heterogeneous disease and the genetic basis underpinning CHD in an overwhelming majority of patients remains unclear. In this study, the coding exons and splice junction sites of the TBX1 gene, which encodes a T-box homeodomain transcription factor essential for proper cardiovascular morphogenesis, were sequenced in 230 unrelated children with CHD. The available family members of the index patient carrying an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were subsequently genotyped for TBX1. The functional effect of the TBX1 mutation was predicted by online program MutationTaster and characterized by using a dual-luciferase reporter assay system. As a result, a novel heterozygous TBX1 mutation, p.Q277X, was identified in an index patient with double outlet right ventricle (DORV) and ventricular septal defect (VSD). Genetic analysis of the proband's available relatives showed that the mutation co-segregated with CHD transmitted in an autosomal dominant pattern with complete penetrance. The nonsense mutation, which was absent in 400 control chromosomes, altered the amino acid that was completely conserved evolutionarily across species and was predicted to be disease-causing by MutationTaster. Biochemical analysis revealed that Q277X-mutant TBX1 lost transcriptional activating function when compared with its wild-type counterpart. This study firstly associates TBX1 loss-of-function mutation with enhanced susceptibility to DORV and VSD in humans, which provides novel insight into the molecular mechanism underlying CHD and suggests potential implications for the development of new preventive and therapeutic strategies for CHD.
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