Abstract
As a transcription factor mainly expressed in cardiovascular system, T-box 20 (TBX20) plays an important role in embryonic cardiovascular system development and adult heart function. Previous studies have identified associations of two SNPs in the T-box DNA-binding domain of TBX20 with congenital heart disease (CHD) in two Caucasian families, but the associations of TBX20 mutations underlying the more common populations with CHD remain to be uncovered. In this study, 25 unrelated Chinese Han neonates with CHD and 25 healthy children as controls were investigated for TBX20 mutations. SNP genotyping was performed by PCR-DNA sequencing. The selected SNPs were well genotyped and SNP rs3999941 was found to be strongly associated with CHD (p = 0.007). The minor allele of rs3999941 showed a high-risk factor for CHD (OR 4.24; 95 % CI 1.41–12.71). Besides, we found a new SNP site located at the 657th nucleotide of the exon 5 of TBX20 gene which may also be associated with CHD, c.657A>C. The frequency was significantly different between two groups (p = 0.011), the minor allele of SNP c.657A>C also showed a risk factor for CHD (OR 2.56; 95 % CI 1.02–6.46). These findings suggested that the TC genotype of SNP rs3999941 and AC genotype of the new SNP c.657A>C in the TBX20 gene may be risk factors for CHD and thus screening of these SNPs may have some implications in the prevention and treatment of CHD in Han Chinese children.
Similar content being viewed by others
References
Ahn D-G, Ruvinsky I, Oates AC, Silver LM, Ho RK (2000) tbx20, a new vertebrate T-box gene expressed in the cranial motor neurons and developing cardiovascular structures in zebrafish. Mech Dev 95:253–258
Andersen TA, Troelsen Kde L, Larsen LA (2014) Of mice and men: molecular genetics of congenital heart disease. Cell Mol Life Sci 71:1327–1352
Brown D, Binder O, Pagratis M, Parr BA, Conlon FL (2003) Developmental expression of the Xenopus laevis Tbx20 orthologue. Dev Genes Evol 212:604–607
Brown DD, Martz SN, Binder O, Goetz SC, Price BM, Smith JC et al (2005) Tbx5 and Tbx20 act synergistically to control vertebrate heart morphogenesis. Development 132:553–563
Cai X, Zhang W, Hu J, Zhang L, Sultana N, Wu B et al (2013) Tbx20 acts upstream of Wnt signaling to regulate endocardial cushion formation and valve remodeling during mouse cardiogenesis. Development 140:3176–3187
Carson CT, Kinzler ER, Parr BA (2000) Tbx12, a novel T-box gene, is expressed during early stages of heart and retinal development. Mech Dev 96:137–140
Cartegni L, Chew SL, Krainer AR (2002) Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet 3:285–298
Digilio MC, Marino B, Giannotti A, Toscano A, Dallapiccola B (1997) Recurrence risk figures for isolated tetralogy of Fallot after screening for 22q11 microdeletion. J Med Genet 34:188–190
Ferencz C, Neill CA, Boughman JA, Rubin JD, Brenner JI, Perry LW (1989) Congenital cardiovascular malformations associated with chromosome abnormalities: an epidemiologic study. J Pediatr 114:79–86
Grech V, Gatt M (1999) Syndromes and malformations associated with congenital heart disease in a population-based study. Int J Cardiol 68:151–156
Greulich F, Rudat C, Kispert A (2011) Mechanisms of T-box gene function in the developing heart. Cardiovasc Res 91:212–222
Hammer S, Toenjes M, Lange M, Fischer JJ, Dunkel I, Mebus S et al (2008) Characterization of TBX20 in human hearts and its regulation by TFAP2. J Cell Biochem 104:1022–1033
Hammer S, Toenjes M, Lange M, Fischer JJ, Dunkel I, Mebus S et al (2008) Characterization of TBX20 in human hearts and its regulation by TFAP2. J Cell Biochem 104:1022–1033
Hariri F, Nemer M, Nemer G (2012) T-box factors: insights into the evolutionary emergence of the complex heart. Ann Med 44:680–693
Hirayama-Yamada K, Kamisago M, Akimoto K, Aotsuka H, Nakamura Y, Tomita H et al (2005) Phenotypes with GATA4 or NKX2.5 mutations in familial atrial septal defect. Am J Med Genet Part A 135:47–52
Hoffman JI (1990) Congenital heart disease: incidence and inheritance. Pediatr Clin North Am 37:25–43
Hoffman J (1995) Incidence of congenital heart disease: II. Prenatal incidence. Pediatr Cardiol 16:155–165
Hoffman JI, Kaplan S (2002) The incidence of congenital heart disease. J Am Coll Cardiol 39:1890–1900
Kenny D, Hijazi ZM (2012) To inhale or to nebulize: treating the pulmonary vascular bed post-operatively in children with congenital heart disease. Cardiol J 19:335–336
Kidd SA (1995) Congenital heart disease: a 10 year cohort. J Paediatr Child Health 31:362
Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV et al (2007) A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science 315:525–528
Kirk EP, Sunde M, Costa MW, Rankin SA, Wolstein O, Castro ML et al (2007) Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy. Am J Hum Genet 81:280–291
Liu C-X, Shen A-D, Li X-F, Jiao W-W, Bai S, Yuan F et al (2009) Association of TBX5 gene polymorphism with ventricular septal defect in the Chinese Han population. Chin Med J 122:30
Nackley AG, Shabalina SA, Tchivileva IE, Satterfield K, Korchynskyi O, Makarov SS et al (2006) Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science 314:1930–1933
Naiche LA, Harrelson Z, Kelly RG, Papaioannou VE (2005) T-box genes in vertebrate development. Annu Rev Genet 39:219–239
Plageman TF, Yutzey KE (2004) Differential expression and function of Tbx5 and Tbx20 in cardiac development. J Biol Chem 279:19026–19034
Posch MG, Gramlich M, Sunde M, Schmitt KR, Lee SH, Richter S et al (2010) A gain-of-function TBX20 mutation causes congenital atrial septal defects, patent foramen ovale and cardiac valve defects. J Med Genet 47:230–235
Posch MG, Gramlich M, Sunde M, Schmitt KR, Lee SH, Richter S et al (2010) A gain-of-function TBX20 mutation causes congenital atrial septal defects, patent foramen ovale and cardiac valve defects. J Med Genet 47:230–235
Qian L, Mohapatra B, Akasaka T, Liu J, Ocorr K, Towbin JA et al (2008) Transcription factor neuromancer/TBX20 is required for cardiac function in Drosophila with implications for human heart disease. Proc Natl Acad Sci 105:19833–19838
Qiao Y, Wanyan H, Xing Q, Xie W, Pang S, Shan J et al (2012) Genetic analysis of the TBX20 gene promoter region in patients with ventricular septal defects. Gene 500:28–31
Ramser J, Ahearn ME, Lenski C, Yariz KO, Hellebrand H, von Rhein M et al (2008) Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy. Am J Hum Genet 82:188–193
Reller MD, Strickland MJ, Riehle-Colarusso T, Mahle WT, Correa A (2008) Prevalence of congenital heart defects in metropolitan Atlanta, 1998–2005. J Pediatr 153:807–813
Reller MD, Strickland MJ, Riehle-Colarusso T, Mahle WT, Correa A (2008) Prevalence of congenital heart defects in metropolitan Atlanta, 1998–2005. J Pediatr 153:807–813
Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB et al (2012) Heart disease and stroke statistics—2012 update a report from the American heart association. Circulation 125:e2–e220
Ryan K, Chin AJ (2003) T-box genes and cardiac development. Birth Defects Res Part C, Embryo Today: Rev 69:25–37
van der Bom T, Zomer AC, Zwinderman AH, Meijboom FJ, Bouma BJ, Mulder BJ (2011) The changing epidemiology of congenital heart disease. Nat Rev Cardiol 8:50–60
Acknowledgments
We thank all the subjects and their families for participation. We also thank members of the Pediatric department for support.
Conflict of interest
The authors declare no competing interests.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
246_2014_1073_MOESM1_ESM.tif
Figure S1 DNA and amino acid sequences of two selected SNPs within the exon 5 of TBX20 gene: rs6950175/c.765C>A/Ile255Ile and rs3999941/c.766T>C/Phe256Leu (From NCBI) (TIFF 1201 kb)
Rights and permissions
About this article
Cite this article
Chen, J., Sun, F., Fu, J. et al. Association of TBX20 Gene Polymorphism with Congenital Heart Disease in Han Chinese Neonates. Pediatr Cardiol 36, 737–742 (2015). https://doi.org/10.1007/s00246-014-1073-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00246-014-1073-5