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

• Published in: Human genomics Vol. 12; no. 1; p. 44
• Main Authors: Xie, Huilin, Zhang, Erge, Hong, Nanchao, Fu, Qihua, Li, Fen, Chen, Sun, Yu, Yu, Sun, Kun
• Format: Journal Article
• Language: English
• Published: England BioMed Central 17-09-2018; BMC
• Subjects: Adenovirus E1A Proteins - genetics; Child, Preschool; Cohort Studies; Congenital defects; Congenital diseases; Conotruncal heart defects; Defects; Dysplasia; Etiology; Female; Gene expression; Gene Expression Regulation; Genetic Predisposition to Disease; Heart; Heart Defects, Congenital - genetics; Heart Defects, Congenital - physiopathology; Humans; Infant; Male; MEF2 Transcription Factors - genetics; Morphogenesis; Mutant Proteins; Mutation; Pathogenesis; Polymorphism, Single Nucleotide - genetics; Primary Research; Promoter Regions, Genetic; Proto-Oncogene Proteins - genetics; T-Box Domain Proteins - genetics; Target sequencing; TBX2; TBX3; Transcription; Transcription factors; Variant; Variant; Target sequencing; TBX3; Conotruncal heart defects; TBX2
• DOI: 10.1186/s40246-018-0176-0
• EISSN: 1479-7364
• ISSN: 1479-7364; 1473-9542

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.
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.
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.