Abstract
Congenital heart disease (CHD) is the most common birth defect occurring in humans and some transcriptional factors have been identified as causative. However, additional mutation analysis of these genes is necessary to develop effective diagnostic and medical treatment methods. We conducted sequence analysis of the coding regions of NKX2.5, GATA4, TBX1, TBX5, TBX20, CFC1 and ZIC3 in 111 Japanese patients with non-syndromic CHD and 9 of their relatives. All patient samples were also analyzed by multiplex ligation-dependent probe amplification using probes involved in chromosome deletion related to CHD. Five novel variations of TBX5, GATA4 and TBX20 were detected in 6 of the patients, whereas none were found in 200 controls. The TBX5 variation p.Pro108Thr, located in the T-box domain, was identified in a patient with tricuspid atresia, an exon–intron boundary variation of GATA4 (IVS4+5G>A) was detected in a Tetralogy of Fallot patient and an 8p23 microdeletion was detected in one patient with atrioventricular septal defect and psychomotor delay. A total of seven non-synonymous polymorphisms were found in the patients and controls. Accumulation of novel variations of genes involving the cardiac development may be required for better understanding of CHD.
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References
Pierpont, M. E., Basson, C. T., Benson, D. W., Gelb, B. D., Giglia, T. M., Goldmuntz, E. et al. Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 115, 3015–3038 (2007).
Garg, V. Insights into the genetic basis of congenital heart disease. Cell. Mol. Life Sci. 63, 1141–1148 (2006).
Schott, J. J., Benson, D. W., Basson, C. T., Pease, W., Silberbach, G. M., Moak, J. P. et al. Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science 281, 108–111 (1998).
Garg, V., Kathiriya, I. S., Barnes, R., Schluterman, M. K., King, I. N., Butler, C. A. et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424, 443–447 (2003).
Yagi, H., Furutani, Y., Hamada, H., Sasaki, T., Asakawa, S., Minoshima, S. et al. Role of TBX1 in human del22q11.2 syndrome. Lancet 362, 1366–1373 (2003).
Basson, C. T., Bachinsky, D. R., Lin, R. C., Levi, T., Elkins, J. A., Soults, J. et al. Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome. Nat. Genet. 15, 30–35 (1997).
Li, Q. Y., Newbury-Ecob, R. A., Terrett, J. A., Wilson, D. I., Curtis, A. R., Yi, C. H. et al. Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat. Genet. 15, 21–29 (1997).
Kirk, E. P., Sunde, M., Costa, M. W., Rankin, S. A., Wolstein, O., Castro, M. L. et al. 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 (2007).
Bamford, R. N., Roessler, E., Burdine, R. D., Saplakoğlu, U., dela Cruz, J., Splitt, M. et al. Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects. Nat. Genet. 26, 365–369 (2000).
Gebbia, M., Ferrero, G. B., Pilia, G., Bassi, M. T., Aylsworth, A., Penman-Splitt, M. et al. X-linked situs abnormalities result from mutations in ZIC3. Nat. Genet. 17, 305–308 (1997).
McCulley, D. J. & Black, B. L. Transcription factor pathways and congenital heart disease. Curr. Top. Dev. Biol. 100, 253–277 (2012).
Xu, Y. J., Chen, S., Zhang, J., Fang, S. H., Guo, Q. Q., Wang, J. et al. Novel TBX1 loss-of-function mutation causes isolated conotruncal heart defects in Chinese patients without 22q11.2 deletion. BMC Med. Genet. 15, 78 (2014).
Brassington, A. M., Sung, S. S., Toydemir, R. M., Le, T., Roeder, A. D., Rutherford, A. E. et al. Expressivity of Holt-Oram syndrome is not predicted by TBX5 genotype. Am. J. Hum. Genet. 73, 74–85 (2003).
Baban, A., Postma, A. V., Marini, M., Trocchio, G., Santilli, A., Pelegrini, M. et al. Identification of TBX5 mutations in a series of 94 patients with Tetralogy of Fallot. Am. J. Med. Genet. A 164, 3100–3107 (2014).
Kodo, K., Nishizawa, T., Furutani, M., Arai, S., Ishihara, K., Oda, M. et al. Genetic analysis of essential cardiac transcription factors in 256 patients with non-syndromic congenital heart defects. Circ. J. 76, 1703–1711 (2012).
Ozcelik, C., Bit-Avragim, N., Panek, A., Gaio, U., Geier, C., Lange, P. E. et al. Mutations in the EGF-CFC gene cryptic are an infrequent cause of congenital heart disease. Pediatr. Cardiol. 27, 695–698 (2006).
McDermott, D. A., Bressan, M. C., He, J., Lee, J. S., Aftimos, S., Brueckner, M. et al. TBX5 genetic testing validates strict clinical criteria for Holt-Oram syndrome. Pediatr. Res. 58, 981–986 (2005).
Boogerd, C. J., Dooijes, D., Ilgun, A., Mathijssen, I. B., Hordijk, R., van de Laar, I. M. et al. Functional analysis of novel TBX5 T-box mutations associated with Holt-Oram syndrome. Cardiovasc. Res. 88, 130–139 (2010).
Cross, S. J., Ching, Y. H., Li, Q. Y., Armstrong-Buisseret, L., Spranger, S., Lyonnet, S. et al. The mutation spectrum in Holt-Oram syndrome. J. Med. Genet. 37, 785–787 (2000).
Basson, C. T., Huang, T., Lin, R. C., Bachinsky, D. R., Weremowicz, S., Vaglio, A. et al. Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations. Proc. Natl Acad. Sci. USA 96, 2919–2924 (1999).
Bonachea, E. M., Zender, G., White, P., Corsmeier, D., Newsom, D., Fitzgerald-Butt, S. et al. Use of a targeted, combinatorial next-generation sequencing approach for the study of bicuspid aortic valve. BMC Med. Genomics 7, 56 (2014).
Fan, C., Duhagon, M. A., Oberti, C., Chen, S., Hiroi, Y., Komuro, I. et al. Novel TBX5 mutations and molecular mechanism for Holt-Oram syndrome. J. Med. Genet. 40, e29 (2003).
Posch, M. G., Gramlich, M., Sunde, M., Schmitt, K. R., Lee, S. H., Richter, S. et al. A gain-of-function TBX20 mutation causes congenital atrial septal defects, patent foramen ovale and cardiac valve defects. J. Med. Genet. 47, 230–235 (2010).
Posch, M. G., Perrot, A., Berger, F. & Ozcelik, C. Molecular genetics of congenital atrial septal defects. Clin. Res. Cardiol. 99, 137–147 (2010).
Qian, L., Mohapatra, B., Akasaka, T., Liu, J., Ocorr, K., Towbin, J. A. et al. Transcription factor neuromancer/TBX20 is required for cardiac function in Drosophila with implications for human heart disease. Proc. Natl Acad. Sci. USA 105, 19833–19838 (2008).
Liu, C., Shen, A., Li, X., Jiao, W., Zhang, X. & Li, Z. T-box transcription factor TBX20 mutations in Chinese patients with congenital heart disease. Eur. J. Med. Genet. 51, 580–587 (2008).
Monroy-Muñoz, I. E., Pérez-Hernández, N., Rodríguez-Pérez, J. M., Muñoz-Medina, J. E., Angeles-Martínez, J., García-Trejo, J. J. et al. Novel mutations in the transcriptional activator domain of the human TBX20 in patients with atrial septal defect. Biomed. Res. Int. 2015, 718786 (2015).
Pan, Y., Geng, R., Zhou, N., Zheng, G. F., Zhao, H., Wang, J. et al. TBX20 loss-of-function mutation contributes to double outlet right ventricle. Int. J. Mol. Med. 35, 1058–1066 (2015).
Wang, E., Sun, S., Qiao, B., Duan, W., Huang, G., An, Y. et al. Identification of functional mutations in GATA4 in patients with congenital heart disease. PLoS ONE 8, e62138 (2013).
Yang, Y. Q., Li, L., Wang, J., Liu, X. Y., Chen, X. Z., Zhang, W. et al. A novel GATA4 loss-of-function mutation associated with congenital ventricular septal defect. Pediatr. Cardiol. 33, 539–546 (2012).
Buratti, E., Chivers, M., Královicová, J., Romano, M., Baralle, M., Krainer, A. R. et al. Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. Nucleic Acids Res. 35, 4250–4263 (2007).
Butler, T. L., Esposito, G., Blue, G. M., Cole, A. D., Costa, M. W., Waddell, L. B. et al. GATA4 mutations in 357 unrelated patients with congenital heart malformation. Genet. Test. Mol. Biomarkers 14, 797–802 (2010).
Tomita-Mitchell, A., Mahnke, D. K., Struble, C. A., Tuffnell, M. E., Stamm, K. D., Hidestrand, M. et al. Human gene copy number spectra analysis in congenital heart malformations. Physiol. Genomics 44, 518–541 (2012).
Devriendt, K., Matthijs, G., Van Dael, R., Gewillig, M., Eyskens, B., Hjalgrim, H. et al. Delineation of the critical deletion region for congenital heart defects, on chromosome 8p23.1. Am. J. Hum. Genet. 64, 1119–1126 (1999).
Wat, M. J., Shchelochkov, O. A., Holder, A. M., Breman, A. M., Dagli, A., Bacino, C. et al. Chromosome 8p23.1 deletions as a cause of complex congenital heart defects and diaphragmatic hernia. Am. J. Med. Genet. A 149A, 1661–1677 (2009).
Stoller, J. Z. & Epstein, J. A. Identification of a novel nuclear localization signal in Tbx1 that is deleted in DiGeorge syndrome patients harboring the 1223delC mutation. Hum. Mol. Genet 14, 885–892 (2005).
Zweier, C., Sticht, H., Aydin-Yaylagül, I., Campbell, C. E. & Rauch, A. Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions. Am. J. Hum. Genet. 80, 510–517 (2007).
Fulcoli, F. G., Huynh, T., Scambler, P. J. & Baldini, A. Tbx1 regulates the BMP-Smad1 pathway in a transcription independent manner. PLoS ONE 4, e6049 (2009).
Yan, Y. T., Gritsman, K., Ding, J., Burdine, R. D., Corrales, J. D., Price, S. M. et al. Conserved requirement for EGF-CFC genes in vertebrate left-right axis formation. Genes. Dev. 13, 2527–2537 (1999).
Gaio, U., Schweickert, A., Fischer, A., Garratt, A. N., Müller, T., Ozcelik, C. et al. A role of the cryptic gene in the correct establishment of the left-right axis. Curr. Biol. 9, 1339–1342 (1999).
Roessler, E., Ouspenskaia, M. V., Karkera, J. D., Vélez, J. I., Kantipong, A., Lacbawan, F. et al. Reduced NODAL signaling strength via mutation of several pathway members including FOXH1 is linked to human heart defects and holoprosencephaly. Am. J. Hum. Genet. 83, 18–29 (2008).
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and grants from the Japan Science and Technology Corporation, Ministry of Health, Labour and Welfare of Japan and the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO). We are grateful to the families and patients who participated in this study. We acknowledge Yoko Miyamoto and Akiko Ohno for their technical support.
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Yoshida, A., Morisaki, H., Nakaji, M. et al. Genetic mutation analysis in Japanese patients with non-syndromic congenital heart disease. J Hum Genet 61, 157–162 (2016). https://doi.org/10.1038/jhg.2015.126
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DOI: https://doi.org/10.1038/jhg.2015.126
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