A Novel TBX1 Loss-of-Function Mutation Associated with Congenital Heart Disease

Abstract

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.

TBX1 loss‑of‑function mutation contributes to congenital conotruncal defects

“…The index patient had a family history of CHD and genetic analysis indicated that the mutation co-segregated with VSD transmitted in an autosomal dominant pattern with complete penetrance. Biochemical analysis revealed that Q277X-mutant TBX1 lost transcriptional activating function when compared with its wild-type counterpart (4). Taken together, these results, together with those of the present study, support that genetically compromised TBX1 confers an enhanced susceptibility of CTD in a minority of cases.…”

“…Heterozygous TBX1-null mice exhibit cardiac, craniofacial, thymic and parathyroid deformities, similar to those observed in patients with severe 22q11DS (50)(51)(52). In addition to syndromic CTD, TBX1 mutations have been causally linked to non-syndromic CTD in humans, including isolated TOF, VSD, PA, DORV, IAA and aortic arch anomalies (4,(53)(54)(55). However, the prevalence and spectrum of TBX1 mutations in patients with other forms of non-syndromic CTD remain unknown.…”

“…If surgery to repair CTD is not performed, patients experience a reduced quality of life, decreased performance during exercise and delayed brain development. CTD may also induce pulmonary hypertension, cardiac enlargement, ventricular dysfunction, heart failure, cardiac arrhythmia and even sudden mortality (2)(3)(4). Advances in therapeutic strategies to treat patients with CTD have resulted in more neonates with CTD surviving into adulthood; however, morbidity and mortality rates remain high in such survivors (5)(6)(7)(8).…”

Whole exome sequencing identifies mutations in 10% of patients with familial non-syndromic cleft lip and/or palate in genes mutated in well-known syndromes

“…Deleterious variants located within the Brachyury T domain (a well-conserved DBD, shared with T-Box family members) are associated with DGS/VCFS (figure 3 and online supplementary table S2) and some variants are associated with isolated congenital heart defects (CHDs) (figure 3 and online supplementary table S2). In vitro investigations by luciferase assay demonstrated that the only identified PTC in the DNA-binding domain of TBX1 p.Glu277*, which co-segregated in a family with CHD, is a LoF variant 33. This variant is distal to our p.Arg269* variant, which manifests as isolated VPI without any cardiac defect.…”

Histone lysine methylation and congenital heart disease: From bench to bedside (Review)

“…TBX1 mutation can lead to DiGeorge syndrome (DGS), which is the most common microdeletion syndrome, and is characterized by congenital cardiac, craniofacial and immune system abnormalities (105). Additionally, Pan et al reported that a novel heterozygous TBX1 mutation, p.Q277X, was identified in an index patient with double outlet right ventricle and ventricular septal defect (106). TBX2 gene is expressed in the myocardium of the atrioventricular canal, outflow tract and inflow tract and plays a critical role in heart chamber formation (107).…”