Identification of TBX2 and TBX3 variants in patients with conotruncal heart defects by target sequencing

Human Genomics

Fen Li¹  Nanchao Hong²  Sun Chen²  Yu Yu²  Erge Zhang²  Kun Sun²  Huilin Xie²  Qihua Fu³ 

[1]Department of Pediatric Cardiology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University

[2]Department of Pediatric Cardiovascular, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University

[3]Medical Laboratory, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University

关键词: TBX2;    TBX3;    Variant;    Conotruncal heart defects;    Target sequencing;   

DOI  :  10.1186/s40246-018-0176-0

来源: DOAJ

【 摘 要 】

Abstract Background Conotruncal heart defects (CTDs) are heterogeneous congenital heart malformations that result from outflow tract dysplasia; however, the genetic determinants underlying CTDs remain unclear. Increasing evidence demonstrates that dysfunctional TBX2 and TBX3 result in outflow tract malformations, implying that both of them are involved in CTD pathogenesis. We screened for TBX2 and TBX3 variants in a large cohort of CTD patients (n = 588) and population-matched healthy controls (n = 300) by target sequencing and genetically analyzed the expression and function of these variants. Results The probably damaging variants p.R608W, p.T249I, and p.R616Q of TBX2 and p.A192T, p.M65L, and p.A562V of TBX3 were identified in CTD patients, but none in controls. All altered amino acids were highly conserved evolutionarily. Moreover, our data suggested that mRNA and protein expressions of TBX2 and TBX3 variants were altered compared with those of the wild-type. We screened PEA3 and MEF2C as novel downstream genes of TBX2 and TBX3, respectively. Functional analysis revealed that TBX2R608W and TBX2R616Q variant proteins further activated HAS2 promoter but failed to activate PEA3 promoter and that TBX3A192T and TBX3A562V variant proteins showed a reduced transcriptional activity over MEF2C promoter. Conclusions Our results indicate that the R608W and R616Q variants of TBX2 as well as the A192T and A562V variants of TBX3 contribute to CTD etiology; this was the first association of variants of TBX2 and TBX3 to CTDs based on a large population.

【 授权许可】

Unknown