Skip to main content
SpringerLink
Log in
Book cover

Genetic Causes of Cardiac Disease pp 169–184Cite as

Complex Genetics and the Etiology of Human Congenital Heart Disease

  • Chapter
  • First Online:

  • 598 Accesses

Part of the book series: Cardiac and Vascular Biology ((Abbreviated title: Card. vasc. biol.,volume 7))

Abstract

The genetic architecture of human congenital heart disease (CHD) is as complex as the phenotypes it produces. The objective of this chapter is to review recent findings on the genetic basis and inheritance patterns of CHD. Rather than provide lists of identified genes, instead we offer a conceptual framework to understand the relationship between genetic variation and CHD. We review recent studies utilizing contemporary techniques, some of which may be difficult to interpret for the nonspecialist. This overview aims to educate students and clinicians, providing a background to understand pertinent genetic literature as it relates to human CHD.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. International Human Genome Sequencing, C. Finishing the euchromatic sequence of the human genome. Nature. 2004;431(7011):931–45.

    Article  CAS  Google Scholar 

  2. Lander ES, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409(6822):860–921.

    Article  CAS  PubMed  Google Scholar 

  3. Venter JC, et al. The sequence of the human genome. Science. 2001;291(5507):1304–51.

    Article  CAS  PubMed  Google Scholar 

  4. An Y, et al. Genome-wide copy number variant analysis for congenital ventricular septal defects in Chinese Han population. BMC Med Genet. 2016;9:2.

    Google Scholar 

  5. Seidman JG, Seidman C. Transcription factor haploinsufficiency: when half a loaf is not enough. J Clin Invest. 2002;109(4):451–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yuan S, Zaidi S, Brueckner M. Congenital heart disease: emerging themes linking genetics and development. Curr Opin Genet Dev. 2013;23(3):352–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jin SC, et al. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nat Genet. 2017;49(11):1593–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zaidi S, et al. De novo mutations in histone-modifying genes in congenital heart disease. Nature. 2013;498(7453):220–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bentham J, Bhattacharya S. Genetic mechanisms controlling cardiovascular development. Ann N Y Acad Sci. 2008;1123:10–9.

    Article  CAS  PubMed  Google Scholar 

  10. Fahed AC, et al. Genetics of congenital heart disease: the glass half empty. Circ Res. 2013;112(4):707–20.

    Article  CAS  PubMed  Google Scholar 

  11. Wild PS, et al. Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function. J Clin Invest. 2017;127(5):1798–812.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Baccarelli A, Rienstra M, Benjamin EJ. Cardiovascular epigenetics: basic concepts and results from animal and human studies. Circ Cardiovasc Genet. 2010;3(6):567–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chowdhury S, et al. Maternal genome-wide DNA methylation patterns and congenital heart defects. PLoS One. 2011;6(1):e16506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Vallaster M, Vallaster CD, Wu SM. Epigenetic mechanisms in cardiac development and disease. Acta Biochim Biophys Sin Shanghai. 2012;44(1):92–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Genomes Project C, et al. A global reference for human genetic variation. Nature. 2015;526(7571):68–74.

    Article  CAS  Google Scholar 

  16. Sudmant PH, et al. An integrated map of structural variation in 2,504 human genomes. Nature. 2015;526(7571):75–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. International HapMap, C. A haplotype map of the human genome. Nature. 2005;437(7063):1299–320.

    Article  CAS  Google Scholar 

  18. Caputo S, et al. Familial recurrence of congenital heart disease in patients with ostium secundum atrial septal defect. Eur Heart J. 2005;26(20):2179–84.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. Spencer CC, et al. Designing genome-wide association studies: sample size, power, imputation, and the choice of genotyping chip. PLoS Genet. 2009;5(5):e1000477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cordell HJ, et al. Genome-wide association study identifies loci on 12q24 and 13q32 associated with tetralogy of Fallot. Hum Mol Genet. 2013;22(7):1473–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Goodship JA, et al. A common variant in the PTPN11 gene contributes to the risk of tetralogy of Fallot. Circ Cardiovasc Genet. 2012;5(3):287–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hu Z, et al. A genome-wide association study identifies two risk loci for congenital heart malformations in Han Chinese populations. Nat Genet. 2013;45(7):818–21.

    Article  CAS  PubMed  Google Scholar 

  24. Stevens KN, et al. Common variation in ISL1 confers genetic susceptibility for human congenital heart disease. PLoS One. 2010;5(5):e10855.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Winston JB, et al. Heterogeneity of genetic modifiers ensures normal cardiac development. Circulation. 2010;121(11):1313–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Prendiville T, Jay PY, Pu WT. Insights into the genetic structure of congenital heart disease from human and murine studies on monogenic disorders. Cold Spring Harb Perspect Med. 2014;4(10):a013946.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rogers MS, D’Amato RJ. The effect of genetic diversity on angiogenesis. Exp Cell Res. 2006;312(5):561–74.

    Article  CAS  PubMed  Google Scholar 

  28. Abou Hassan OK, et al. NKX2-5 mutations in an inbred consanguineous population: genetic and phenotypic diversity. Sci Rep. 2015;5:8848.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. McElhinney DB, et al. NKX2.5 mutations in patients with congenital heart disease. J Am Coll Cardiol. 2003;42(9):1650–5.

    Article  CAS  PubMed  Google Scholar 

  30. Bruneau BG, 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.

    Article  CAS  PubMed  Google Scholar 

  31. Gao J, et al. From genotype to phenotype: cytochrome P450 2D6-mediated drug clearance in humans. Mol Pharm. 2017;14(3):649–57.

    Article  CAS  PubMed  Google Scholar 

  32. Ur Rasheed MS, Mishra AK, Singh MP. Cytochrome P450 2D6 and Parkinson’s disease: polymorphism, metabolic role, risk and protection. Neurochem Res. 2017;42(12):3353–61.

    Article  CAS  PubMed  Google Scholar 

  33. Lessard E, et al. Role of CYP2D6 in the N-hydroxylation of procainamide. Pharmacogenetics. 1997;7(5):381–90.

    Article  CAS  PubMed  Google Scholar 

  34. Mottet F, Vardeny O, de Denus S. Pharmacogenomics of heart failure: a systematic review. Pharmacogenomics. 2016;17(16):1817–58.

    Article  CAS  PubMed  Google Scholar 

  35. Gaynor JW, et al. Validation of association of the apolipoprotein E epsilon2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants. J Thorac Cardiovasc Surg. 2014;148(6):2560–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gaynor JW, et al. Apolipoprotein E genotype modifies the risk of behavior problems after infant cardiac surgery. Pediatrics. 2009;124(1):241–50.

    Article  PubMed  Google Scholar 

  37. Kim DS, et al. Patient genotypes impact survival after surgery for isolated congenital heart disease. Ann Thorac Surg. 2014;98(1):104–10; discussion 110–1.

    Google Scholar 

  38. Mital S, et al. Renin-angiotensin-aldosterone genotype influences ventricular remodeling in infants with single ventricle. Circulation. 2011;123(21):2353–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Teer JK, Mullikin JC. Exome sequencing: the sweet spot before whole genomes. Hum Mol Genet. 2010;19(R2):R145–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cirulli ET, Goldstein DB. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet. 2010;11(6):415–25.

    Article  CAS  PubMed  Google Scholar 

  41. Veeramah KR, Hammer MF. The impact of whole-genome sequencing on the reconstruction of human population history. Nat Rev Genet. 2014;15(3):149–62.

    Article  CAS  PubMed  Google Scholar 

  42. Chung JH, et al. Whole-genome sequencing and integrative genomic analysis approach on two 22q11.2 deletion syndrome family trios for genotype to phenotype correlations. Hum Mutat. 2015;36(8):797–807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Krupp DR, et al. Exonic mosaic mutations contribute risk for autism spectrum disorder. Am J Hum Genet. 2017;101(3):369–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Menezes J, et al. Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm. Leukemia. 2014;28(4):823–9.

    Article  CAS  PubMed  Google Scholar 

  45. Andersen TA, Troelsen Kde L, Larsen LA. Of mice and men: molecular genetics of congenital heart disease. Cell Mol Life Sci. 2014;71(8):1327–52.

    Article  CAS  PubMed  Google Scholar 

  46. Stallmeyer B, et al. Mutational spectrum in the cardiac transcription factor gene NKX2.5 (CSX) associated with congenital heart disease. Clin Genet. 2010;78(6):533–40.

    Article  CAS  PubMed  Google Scholar 

  47. Dewey FE, et al. Gene coexpression network topology of cardiac development, hypertrophy, and failure. Circ Cardiovasc Genet. 2011;4(1):26–35.

    Article  CAS  PubMed  Google Scholar 

  48. Lage K, et al. Genetic and environmental risk factors in congenital heart disease functionally converge in protein networks driving heart development. Proc Natl Acad Sci USA. 2012;109(35):14035–40.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Sperling SR. Systems biology approaches to heart development and congenital heart disease. Cardiovasc Res. 2011;91(2):269–78.

    Article  CAS  PubMed  Google Scholar 

  50. Esposito G, et al. Somatic mutations in NKX2-5, GATA4, and HAND1 are not a common cause of tetralogy of Fallot or hypoplastic left heart. Am J Med Genet A. 2011;155A(10):2416–21.

    Article  CAS  PubMed  Google Scholar 

  51. Zheng J, et al. Investigation of somatic NKX2-5 mutations in Chinese children with congenital heart disease. Int J Med Sci. 2015;12(7):538–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. van der Linde D, et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol. 2011;58(21):2241–7.

    Article  PubMed  Google Scholar 

  53. Sifrim A, et al. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nat Genet. 2016;48(9):1060–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kleinjan DA, van Heyningen V. Long-range control of gene expression: emerging mechanisms and disruption in disease. Am J Hum Genet. 2005;76(1):8–32.

    Article  CAS  PubMed  Google Scholar 

  55. West AG, Fraser P. Remote control of gene transcription. Hum Mol Genet. 2005;14(1):R101–11.

    Article  CAS  PubMed  Google Scholar 

  56. Velagaleti GV, et al. Position effects due to chromosome breakpoints that map approximately 900 Kb upstream and approximately 1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia. Am J Hum Genet. 2005;76(4):652–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Saitsu H, Shiota K, Ishibashi M. Analysis of Fibroblast growth factor 15 cis-elements reveals two conserved enhancers which are closely related to cardiac outflow tract development. Mech Dev. 2006;123(9):665–73.

    Article  CAS  PubMed  Google Scholar 

  58. Strahle U, Rastegar S. Conserved non-coding sequences and transcriptional regulation. Brain Res Bull. 2008;75(2-4):225–30.

    Article  CAS  PubMed  Google Scholar 

  59. Carey AS, et al. Effect of copy number variants on outcomes for infants with single ventricle heart defects. Circ Cardiovasc Genet. 2013;6(5):444–51.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Glessner JT, et al. Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data. Circ Res. 2014;115(10):884–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Warburton D, et al. The contribution of de novo and rare inherited copy number changes to congenital heart disease in an unselected sample of children with conotruncal defects or hypoplastic left heart disease. Hum Genet. 2014;133(1):11–27.

    Article  PubMed  Google Scholar 

  62. Gelb BD, Chung WK. Complex genetics and the etiology of human congenital heart disease. Cold Spring Harb Perspect Med. 2014;4(7):a013953.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Cowan JR, Ware SM. Genetics and genetic testing in congenital heart disease. Clin Perinatol. 2015;42(2):373–93, ix

    Article  PubMed  Google Scholar 

  64. Geng J, et al. Chromosome microarray testing for patients with congenital heart defects reveals novel disease causing loci and high diagnostic yield. BMC Genomics. 2014;15:1127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Miller DT, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Arndt AK, MacRae CA. Genetic testing in cardiovascular diseases. Curr Opin Cardiol. 2014;29(3):235–40.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Landis BJ, Ware SM. The current landscape of genetic testing in cardiovascular malformations: opportunities and challenges. Front Cardiovasc Med. 2016;3:22.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Aiyagari R, et al. Impact of pre-stage II hemodynamics and pulmonary artery anatomy on 12-month outcomes in the Pediatric Heart Network Single Ventricle Reconstruction trial. J Thorac Cardiovasc Surg. 2014;148(4):1467–74.

    Article  PubMed  Google Scholar 

  69. Tomita-Mitchell A, et al. Human gene copy number spectra analysis in congenital heart malformations. Physiol Genomics. 2012;44(9):518–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Yale University School of Medicine, New Haven, CT, USA

    Peter J. Gruber

  2. Children’s Hospital of Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Richard W. Kim

Authors
  1. Richard W. Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter J. Gruber
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter J. Gruber .

Editor information

Editors and Affiliations

  1. IIEG, University of Lubeck, Lübeck, Germany

    Jeanette Erdmann

  2. I Medical Dept (Cardiology), Klinikum Rechts der Isar of the Technical University Munich, München, Bayern, Germany

    Alessandra Moretti

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Kim, R.W., Gruber, P.J. (2019). Complex Genetics and the Etiology of Human Congenital Heart Disease. In: Erdmann, J., Moretti, A. (eds) Genetic Causes of Cardiac Disease. Cardiac and Vascular Biology, vol 7. Springer, Cham. https://doi.org/10.1007/978-3-030-27371-2_5

Download citation

Publish with us

Policies and ethics

Search

Navigation