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Molecular Basis of Cardiac Development and Congenital Heart Disease

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Translational Cardiology

Part of the book series: Molecular and Translational Medicine ((MOLEMED))

Abstract

Cardiovascular malformations are the most common type of birth defect and result in significant mortality worldwide. The etiology for the majority of these anomalies remains unknown. The heart is the first organ to form, and the process of cardiac development has been well described in multiple species. More recently, advances in the characterization of the molecular pathways critical for normal cardiac development has led to the identification of numerous genes necessary for this complex morphogenetic process. This work has aided the discovery of an increasing number of genetic contributors being implicated as the cause of human cardiovascular malformations. This chapter summarizes normal cardiac development and outlines the discoveries of the genetic causes of congenital heart disease. We begin by summarizing the stages of cardiac development from early cardiomyocyte specification to the later stages of chamber and septa formation, valvulogenesis, and development of the outflow tracts. Next, we discuss the roles of the multiple cellular contributors that are necessary for normal heart formation. We finish this chapter by highlighting the intricacies of the molecular pathways regulating cardiac embryogenesis that are now beginning to be elucidated and how they have impacted human disease.

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References

  1. Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002;39(12):1890–900.

    PubMed  Google Scholar 

  2. Gilboa SM, Salemi JL, Nembhard WN, et al. Mortality resulting from congenital heart disease among children and adults in the United States, 1999 to 2006. Circulation. 2010;122(22):2254–63.

    PubMed  Google Scholar 

  3. Bruneau BG. The developmental genetics of congenital heart disease. Nature. 2008;451(7181): 943–8.

    PubMed  CAS  Google Scholar 

  4. Ferencz C, Rubin J, Loffredo CA, Magee CM. The epidemiology of congenital heart disease, The Baltimore-Washington Infant Study (1981–1989), Vol 4. Mount Kisco, NY: Future Publishing Co. Inc.; 1993.

    Google Scholar 

  5. Buckingham M, Meilhac S, Zaffran S. Building the mammalian heart from two sources of myocardial cells. Nat Rev Genet. 2005;6(11):826–35.

    PubMed  CAS  Google Scholar 

  6. Cai CL, Liang X, Shi Y, et al. Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell. 2003;5(6):877–89.

    PubMed  CAS  Google Scholar 

  7. Schultheiss TM, Xydas S, Lassar AB. Induction of avian cardiac myogenesis by anterior endoderm. Development. 1995;121(12):4203–14.

    PubMed  CAS  Google Scholar 

  8. Schneider VA, Mercola M. Wnt antagonism initiates cardiogenesis in Xenopus laevis. Genes Dev. 2001;15(3):304–15.

    PubMed  CAS  Google Scholar 

  9. Marvin MJ, Di Rocco G, Gardiner A, et al. Inhibition of Wnt activity induces heart formation from posterior mesoderm. Genes Dev. 2001;15(3):316–27.

    PubMed  CAS  Google Scholar 

  10. Zaffran S, Frasch M. Early signals in cardiac development. Circ Res. 2002;91(6):457–69.

    PubMed  CAS  Google Scholar 

  11. Takeuchi JK, Bruneau BG. Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors. Nature. 2009;459(7247):708–11.

    PubMed  CAS  Google Scholar 

  12. Lyons I, Parsons LM, Hartley L, et al. Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5. Genes Dev. 1995;9(13):1654–66.

    PubMed  CAS  Google Scholar 

  13. Tanaka M, Chen Z, Bartunkova S, et al. The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstream of multiple genes essential for heart development. Development. 1999;126(6):1269–80.

    PubMed  CAS  Google Scholar 

  14. Molkentin JD. The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression. J Biol Chem. 2000;275(50):38949–52.

    PubMed  CAS  Google Scholar 

  15. Molkentin JD, Lin Q, Duncan SA, Olson EN. Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Genes Dev. 1997;11(8):1061–72.

    PubMed  CAS  Google Scholar 

  16. Kuo CT, Morrisey EE, Anandappa R, et al. GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev. 1997;11(8):1048–60.

    PubMed  CAS  Google Scholar 

  17. Pu WT, Ishiwata T, Juraszek AL, et al. GATA4 is a dosage-sensitive regulator of cardiac morphogenesis. Dev Biol. 2004;275(1):235–44.

    PubMed  CAS  Google Scholar 

  18. Zeisberg EM, Ma Q, Juraszek AL, et al. Morphogenesis of the right ventricle requires myocardial expression of Gata4. J Clin Invest. 2005;115(6):1522–31.

    PubMed  CAS  Google Scholar 

  19. Rivera-Feliciano J, Lee KH, Kong SW, et al. Development of heart valves requires Gata4 expression in endothelial-derived cells. Development. 2006;133(18):3607–18.

    PubMed  CAS  Google Scholar 

  20. Zhao R, Watt AJ, Battle MA, et al. Loss of both GATA4 and GATA6 blocks cardiac myocyte differentiation and results in acardia in mice. Dev Biol. 2008;317(2):614–9.

    PubMed  CAS  Google Scholar 

  21. Singh MK, Li Y, Li S, et al. Gata4 and Gata5 cooperatively regulate cardiac myocyte proliferation in mice. J Biol Chem. 2010;285(3):1765–72.

    PubMed  CAS  Google Scholar 

  22. Plageman Jr TF, Yutzey KE. T-box genes and heart development: putting the “T” in heart. Dev Dyn. 2005;232(1):11–20.

    PubMed  CAS  Google Scholar 

  23. Bruneau BG, Nemer G, Schmitt JP, et al. A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease. Cell. 2001;106(6):709–21.

    PubMed  CAS  Google Scholar 

  24. Stennard FA, Costa MW, Lai D, et al. Murine T-box transcription factor Tbx20 acts as a repressor during heart development, and is essential for adult heart integrity, function and adaptation. Development. 2005;132(10):2451–62.

    PubMed  CAS  Google Scholar 

  25. Singh MK, Christoffels VM, Dias JM, et al. Tbx20 is essential for cardiac chamber differentiation and repression of Tbx2. Development. 2005;132(12):2697–707.

    PubMed  CAS  Google Scholar 

  26. Bruneau BG. Transcriptional regulation of vertebrate cardiac morphogenesis. Circ Res. 2002;90(5):509–19.

    PubMed  Google Scholar 

  27. Olson EN. Gene regulatory networks in the evolution and development of the heart. Science. 2006;313(5795):1922–7.

    PubMed  CAS  Google Scholar 

  28. Olivey HE, Compton LA, Barnett JV. Coronary vessel development: the epicardium delivers. Trends Cardiovasc Med. 2004;14(6):247–51.

    PubMed  CAS  Google Scholar 

  29. Fishman MC, Olson EN. Parsing the heart: genetic modules for organ assembly. Cell. 1997;91(2):153–6.

    PubMed  CAS  Google Scholar 

  30. Watt AJ, Battle MA, Li J, Duncan SA. GATA4 is essential for formation of the proepicardium and regulates cardiogenesis. Proc Natl Acad Sci USA. 2004;101(34):12573–8.

    PubMed  CAS  Google Scholar 

  31. Saga Y, Miyagawa-Tomita S, Takagi A, et al. MesP1 is expressed in the heart precursor cells and required for the formation of a single heart tube. Development. 1999;126(15):3437–47.

    PubMed  CAS  Google Scholar 

  32. Ramsdell AF. Left-right asymmetry and congenital cardiac defects: getting to the heart of the matter in vertebrate left-right axis determination. Dev Biol. 2005;288(1):1–20.

    PubMed  CAS  Google Scholar 

  33. Franco D, Campione M. The role of Pitx2 during cardiac development. Linking left-right signaling and congenital heart diseases. Trends Cardiovasc Med. 2003;13(4):157–63.

    PubMed  CAS  Google Scholar 

  34. Christoffels VM, Habets PE, Franco D, et al. Chamber formation and morphogenesis in the developing mammalian heart. Dev Biol. 2000;223(2):266–78.

    PubMed  CAS  Google Scholar 

  35. Markwald RR, Fitzharris TP, Smith WN. Structural analysis of endocardial cytodifferentiation. Dev Biol. 1975;42(1):160–80.

    PubMed  CAS  Google Scholar 

  36. Brown CB, Boyer AS, Runyan RB, Barnett JV. Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart. Science. 1999;283(5410):2080–2.

    PubMed  CAS  Google Scholar 

  37. Nakajima Y, Yamagishi T, Hokari S, Nakamura H. Mechanisms involved in valvuloseptal endocardial cushion formation in early cardiogenesis: roles of transforming growth factor (TGF)-beta and bone morphogenetic protein (BMP). Anat Rec. 2000;258(2): 119–27.

    PubMed  CAS  Google Scholar 

  38. Timmerman LA, Grego-Bessa J, Raya A, et al. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev. 2004;18(1):99–115.

    PubMed  CAS  Google Scholar 

  39. Yutzey KE, Colbert M, Robbins J. Ras-related signaling pathways in valve development: ebb and flow. Physiology (Bethesda). 2005;20:390–7.

    CAS  Google Scholar 

  40. Chang CP, Neilson JR, Bayle JH, et al. A field of myocardial-endocardial NFAT signaling underlies heart valve morphogenesis. Cell. 2004;118(5):649–63.

    PubMed  CAS  Google Scholar 

  41. Wu B, Wang Y, Lui W, Langworthy M, Tompkins KL, Hatzopoulos AK, Baldwin HS, Zhou B. Nfatc1 coordinates valve endocardial cell lineage development required for heart valve formation. Circ Res. 2011;109(2):183–92.

    PubMed  CAS  Google Scholar 

  42. Gaussin V, Van de Putte T, Mishina Y, et al. Endocardial cushion and myocardial defects after cardiac myocyte-specific conditional deletion of the bone morphogenetic protein receptor ALK3. Proc Natl Acad Sci USA. 2002;99(5):2878–83.

    PubMed  CAS  Google Scholar 

  43. Jiao K, Kulessa H, Tompkins K, et al. An essential role of Bmp4 in the atrioventricular septation of the mouse heart. Genes Dev. 2003;17(19):2362–7.

    PubMed  CAS  Google Scholar 

  44. Webb S, Brown NA, Anderson RH. Formation of the atrioventricular septal structures in the normal mouse. Circ Res. 1998;82(6):645–56.

    PubMed  CAS  Google Scholar 

  45. Kirby ML, Waldo KL. Role of neural crest in congenital heart disease. Circulation. 1990;82(2):332–40.

    PubMed  CAS  Google Scholar 

  46. Stoller JZ, Epstein JA. Cardiac neural crest. Semin Cell Dev Biol. 2005;16(6):704–15.

    PubMed  CAS  Google Scholar 

  47. GargV YC, Hu T, et al. Tbx1, a DiGeorge syndrome candidate gene, is regulated by sonic Hedgehog during pharyngeal arch development. Dev Biol. 2001;235(1):62–73.

    Google Scholar 

  48. Frank DU, Fotheringham LK, Brewer JA, et al. An Fgf8 mouse mutant phenocopies human 22q11 deletion syndrome. Development. 2002;129(19):4591–603.

    PubMed  CAS  Google Scholar 

  49. Lindsay EA, Vitelli F, Su H, et al. Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice. Nature. 2001;410(6824):97–101.

    PubMed  CAS  Google Scholar 

  50. Washington Smoak I, Byrd NA, Abu-Issa R, et al. Sonic Hedgehog is required for cardiac outflow tract and neural crest cell development. Dev Biol. 2005;283(2):357–72.

    PubMed  CAS  Google Scholar 

  51. Svensson EC, Huggins GS, Lin H, et al. A Syndrome of tricuspid atresia in mice with a targeted mutation of the gene encoding Fog-2. Nat Genet. 2000;25(3):353–6.

    PubMed  CAS  Google Scholar 

  52. Tevosian SG, Deconinck AE, Tanaka M, et al. Fog-2, a cofactor for GATA transcription factors, is essential for heart morphogenesis and development of coronary vessels from epicardium. Cell. 2000;101(7):729–39.

    PubMed  CAS  Google Scholar 

  53. Levin M, Johnson RL, Stern CD, et al. A molecular pathway determining left-right asymmetry in chick embryogenesis. Cell. 1995;82(5):803–14.

    PubMed  CAS  Google Scholar 

  54. Isaac A, Sargent MG, Cooke J. Control of vertebrate left-right asymmetry by a snail-related zinc finger gene. Science. 1997;275(5304):1301–4.

    PubMed  CAS  Google Scholar 

  55. Piedra ME, Icardo JM, Albajar M, et al. Pitx2 participates in the late phase of the pathway controlling left-right asymmetry. Cell. 1998;94(3):319–24.

    PubMed  CAS  Google Scholar 

  56. Kathiriya IS, Srivastava D. Left-right asymmetry and cardiac looping: implications for cardiac development and congenital heart disease. Am J Med Genet. 2000;97(4):271–9.

    PubMed  CAS  Google Scholar 

  57. Nonaka S, Tanaka Y, Okada Y, et al. Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell. 1998;95(6):829–37.

    PubMed  CAS  Google Scholar 

  58. Brueckner M, D’Eustachio P, Horwich AL. Linkage mapping of a mouse gene, iv, that controls left-right asymmetry of the heart and viscera. Proc Natl Acad Sci USA. 1989;86(13):5035–8.

    PubMed  CAS  Google Scholar 

  59. Supp DM, Brueckner M, Kuehn MR, et al. Targeted deletion of the ATP binding domain of left-right dynein confirms its role in specifying development of left-right asymmetries. Development. 1999;126(23):5495–504.

    PubMed  CAS  Google Scholar 

  60. Supp DM, Witte DP, Potter SS, Brueckner M. Mutation of an axonemal dynein affects left-right asymmetry in inversus viscerum mice. Nature. 1997;389(6654):963–6.

    PubMed  CAS  Google Scholar 

  61. Nonaka S, Shiratori H, Saijoh Y, Hamada H. Determination of left-right patterning of the mouse embryo by artificial nodal flow. Nature. 2002;418(6893):96–9.

    PubMed  CAS  Google Scholar 

  62. McGrath J, Somlo S, Makova S, et al. Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell. 2003;114(1):61–73.

    PubMed  CAS  Google Scholar 

  63. Basu B, Brueckner M. Cilia multifunctional organelles at the center of vertebrate left-right asymmetry. Curr Top Dev Biol. 2008;85:151–74.

    PubMed  CAS  Google Scholar 

  64. Bernstein D. Evaluation of the cardiovascular system. In: Behrman RE, Kliegman RM, Jenson HB, editors. Nelson textbook of pediatrics. 17th ed. Philadelphia: Saunders; 2004. p. 1481–8.

    Google Scholar 

  65. Pierpont ME, Basson CT, Benson Jr DW, 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. 2007;115(23):3015–38.

    PubMed  Google Scholar 

  66. Scambler PJ. The 22q11 deletion syndromes. Hum Mol Genet. 2000;9(16):2421–6.

    PubMed  CAS  Google Scholar 

  67. Goldmuntz E, Clark BJ, Mitchell LE, et al. Frequency of 22q11 deletions in patients with conotruncal defects. J Am Coll Cardiol. 1998;32(2):492–8.

    PubMed  CAS  Google Scholar 

  68. Ewart AK, Morris CA, Atkinson D, et al. Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet. 1993;5(1):11–6.

    PubMed  CAS  Google Scholar 

  69. Ewart AK, Jin W, Atkinson D, et al. Supravalvular aortic stenosis associated with a deletion disrupting the elastin gene. J Clin Invest. 1994;93(3):1071–7.

    PubMed  CAS  Google Scholar 

  70. Li DY, Toland AE, Boak BB, et al. Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis. Hum Mol Genet. 1997;6(7):1021–8.

    PubMed  CAS  Google Scholar 

  71. Redon R, Ishikawa S, Fitch KR, et al. Global variation in copy number in the human genome. Nature. 2006;444(7118):444–54.

    PubMed  CAS  Google Scholar 

  72. Vissers LE, van Ravenswaaij CM, Admiraal R, et al. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet. 2004;36(9):955–7.

    PubMed  CAS  Google Scholar 

  73. Lalani SR, Safiullah AM, Fernbach SD, et al. Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation. Am J Hum Genet. 2006;78(2):303–14.

    PubMed  CAS  Google Scholar 

  74. Bajpai R, Chen DA, Rada-Iglesias A, et al. CHD7 cooperates with PBAF to control multipotent neural crest formation. Nature. 2010;463(7283):958–62.

    PubMed  CAS  Google Scholar 

  75. Randall V, McCue K, Roberts C, et al. J Clin Invest. 2009;119(11):3301–10.

    PubMed  CAS  Google Scholar 

  76. Thienpont B, Mertens L, de Ravel T, et al. Submicroscopic chromosomal imbalances detected by array-CGH are a frequent cause of congenital heart defects in selected patients. Eur Heart J. 2007;28(22):2778–84.

    PubMed  CAS  Google Scholar 

  77. Richards AA, Santos LJ, Nichols HA, et al. Cryptic chromosomal abnormalities identified in children with congenital heart disease. Pediatr Res. 2008;64(4):358–63.

    PubMed  Google Scholar 

  78. Miller DT, Adam MF, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749–64.

    PubMed  CAS  Google Scholar 

  79. Erdogan F, Larsen LA, Zhang L, et al. High frequency of submicroscopic genomic aberrations detected by tiling path array comparative genome hybridisation in patients with isolated congenital heart disease. J Med Genet. 2008;45(11):704–9.

    PubMed  CAS  Google Scholar 

  80. Greenway SC, Pereira AC, Lin JC, et al. De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot. Nat Genet. 2009;41:931–5.

    PubMed  CAS  Google Scholar 

  81. Dietz HC, Cutting GR, Pyeritz RE, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 1991;352(6333):337–9.

    PubMed  CAS  Google Scholar 

  82. Basson CT, Cowley GS, Solomon SD, et al. The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome). N Engl J Med. 1994;330(13):885–91.

    PubMed  CAS  Google Scholar 

  83. Basson CT, Bachinsky DR, Lin RC, et al. Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet. 1997;15(1):30–5.

    PubMed  CAS  Google Scholar 

  84. Chen B, Bronson RT, Klaman LD, et al. Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis. Nat Genet. 2000;24(3):296–9.

    PubMed  CAS  Google Scholar 

  85. Tartaglia M, Mehler EL, Goldberg R, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001;29(4):465–8.

    PubMed  CAS  Google Scholar 

  86. Aoki Y, Niihori T, Narumi Y, et al. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum Mutat. 2008;29(8):992–1006.

    PubMed  CAS  Google Scholar 

  87. Schubbert S, Bollag G, Shannon K. Deregulated Ras signaling in developmental disorders: new tricks for an old dog. Curr Opin Genet Dev. 2007;17(1):15–22.

    PubMed  CAS  Google Scholar 

  88. Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet. 1997;16(3):243–51.

    PubMed  CAS  Google Scholar 

  89. Oda T, Elkahloun AG, Pike BL, et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet. 1997;16(3):235–42.

    PubMed  CAS  Google Scholar 

  90. McDaniell R, Warthen DM, Sanchez-Lara PA, et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet. 2006;79(1):169–73.

    PubMed  CAS  Google Scholar 

  91. Satoda M, Zhao F, Diaz GA, et al. Mutations in TFAP2B cause Char syndrome, a familial form of patent ductus arteriosus. Nat Genet. 2000;25(1):42–6.

    PubMed  CAS  Google Scholar 

  92. Gebbia M, Ferrero GB, Pilia G, et al. X-linked situs abnormalities result from mutations in ZIC3. Nat Genet. 1997;17(3):305–8.

    PubMed  CAS  Google Scholar 

  93. Purandare SM, Ware SM, Kwan KM, et al. A complex syndrome of left-right axis, central nervous system and axial skeleton defects in Zic3 mutant mice. Development. 2002;129(9): 2293–302.

    PubMed  CAS  Google Scholar 

  94. Sutherland MJ, Ware SM. Disorders of left-right asymmetry: heterotaxy and situs inversus. Am J Med Genet C Semin Med Genet. 2009;151C(4):307–17.

    PubMed  CAS  Google Scholar 

  95. Schott JJ, Benson DW, Basson CT, et al. Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science. 1998;281(5373):108–11.

    PubMed  CAS  Google Scholar 

  96. Garg V, Kathiriya IS, Barnes R, et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature. 2003;424(6947):443–7.

    PubMed  CAS  Google Scholar 

  97. Ching YH, Ghosh TK, Cross SJ, et al. Mutation in myosin heavy chain 6 causes atrial septal defect. Nat Genet. 2005;37(4):423–8.

    PubMed  CAS  Google Scholar 

  98. Maitra M, Schluterman MK, Nichols H, et al. Interaction of Gata4 and Tbx5 is critical for normal cardiac development. Dev Biol. 2009;326(2):368–77.

    PubMed  CAS  Google Scholar 

  99. Kodo K, Nishizawa T, Furutani M, et al. GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling. Proc Natl Acad Sci USA. 2009;106(33): 13933–8.

    PubMed  CAS  Google Scholar 

  100. Kirk EP, Sunde M, Costa MW, 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. 2007;81(2):280–91.

    PubMed  CAS  Google Scholar 

  101. Robinson SW, Morris CD, Goldmuntz E, et al. Missense mutations in CRELD1 are associated with cardiac atrioventricular septal defects. Am J Hum Genet. 2003;72(4):1047–52.

    PubMed  CAS  Google Scholar 

  102. Roberts KE, McElroy JJ, Wong WP, et al. BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur Respir J. 2004;24(3):371–4.

    PubMed  CAS  Google Scholar 

  103. Smith KA, Joziasse IC, Chocron S, et al. Dominant-negative ALK2 allele associates with congenital heart defects. Circulation. 2009;119(24):3062–9.

    PubMed  CAS  Google Scholar 

  104. Garg V, Muth AN, Ransom JF, et al. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005;437(7056):270–4.

    PubMed  CAS  Google Scholar 

  105. Muncke N, Jung C, Rudiger H, et al. Missense mutations and gene interruption in PROSIT240, a novel TRAP240-like gene, in patients with congenital heart defect (transposition of the great arteries). Circulation. 2003;108(23):2843–50.

    PubMed  CAS  Google Scholar 

  106. Goldmuntz E, Geiger E, Benson DW. NKX2.5 mutations in patients with tetralogy of Fallot. Circulation. 2001;104(21):2565–8.

    PubMed  CAS  Google Scholar 

  107. Schluterman MK, Krysiak AE, Kathiriya IS, et al. Screening and biochemical analysis of GATA4 sequence variations in patients with congenital heart disease. Am J Med Genet A. 2007;143(8):817–23.

    Google Scholar 

  108. Rajagopal SK, Ma Q, Obler D, et al. Spectrum of heart disease associated with murine and human GATA4 mutation. J Mol Cell Cardiol. 2007;43(6):677–85.

    PubMed  CAS  Google Scholar 

  109. Tomita-Mitchell A, Maslen CL, Morris CD, et al. GATA4 sequence variants in patients with congenital heart disease. J Med Genet. 2007;44(12):779–83.

    PubMed  CAS  Google Scholar 

  110. Maitra M, Koenig S, Srivastava D, Garg V. GATA6 sequence variations in human congenital heart disease. Pediatr Res. 2010;68(4):281–5.

    PubMed  CAS  Google Scholar 

  111. Wessels MW, Willems PJ. Genetic factors in non-syndromic congenital heart malformations. Clin Genet. 2010;78(2):103–23.

    PubMed  CAS  Google Scholar 

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Acknowledgments

The author would like to thank J. Suehs for figure illustrations and S.N. Koenig for assistance with manuscript preparation. V.G. is funded by grants from the National Institutes of Health and the Children’s Heart Foundation.

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  1. Department of Pediatrics, The Ohio State University, Nationwide Children’s Hospital, 700 Children’s Drive, Room W302, Columbus, OH, 43221, USA

    Vidu Garg

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  1. , The University of North Carolina, McAllister Heart Institute, 6022 - Burnett Womack Building, Chapel Hill, 27599-7075, North Carolina, USA

    Cam Patterson

  2. , The University of North Carolina, McAllister Heart Institute, 103 Mason Farm Road, Chapel Hill, 27599-7525, USA

    Monte S. Willis

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Garg, V. (2012). Molecular Basis of Cardiac Development and Congenital Heart Disease. In: Patterson, C., Willis, M. (eds) Translational Cardiology. Molecular and Translational Medicine. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-891-7_10

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