At the Heart of a Complex Disease ‘Molecular Genetics of Congenital Heart Disease’

Abstract

Congenital heart disease (CHD) is the most common type of birth defect and affects almost 1% of the general population. Compared to other rare congenital disorders, CHD rarely shows strictly Mendelian inheritance patterns. Human genetic studies have revealed that multiple genes contribute to the disease in pathways, which affect early cardiac development. Despite recent large‐scale efforts to identify causal genes for CHD, the majority of cases remain enigmatic. The challenges in identifying genotype–phenotype relationships in CHD suggest a more complex pattern of inheritance, where structural as well as single nucleotide variants contribute to the disease and modifiers tune the spectrum of cardiac malformations expressed. Here, we review the current state of genetic research in CHD and discuss the challenges in moving variant identification in CHD into the personal genomics era.

Key Concepts

  • Congenital heart disease (CHD) is a complex developmental phenotype with many genes contributing to its etiology.
  • Single nucleotide polymorphisms (SNPs) as well as structural variants contribute to the burden of CHD in the population.
  • Loss of function variants (LOF) and missense mutations can have different impacts during cardiac development, thus leading to different CHD phenotypes.
  • Genetic factors for congenital heart malformations can be inherited autosomal recessive, autosomal dominant, X‐linked or show non‐Mendelian patterns in families.
  • Genetic background can alter the manifestation of CHD and lead to different CHD subtypes or buffer against disease.

Keywords: congenital heart disease; heart development; genetic background; oligogenic inheritance; personalised genomics; exome sequencing; phenotypic heterogeneity; Notch signalling

Figure 1. Population prevalence and candidate genes for different subtypes of CHD (congenital heart disease). Overview of prevalence of congenital heart disease in the general population according to Fahed et al. and genetic factors associated with common right‐ and left‐sided cardiac malformations.
Figure 2. Non‐Mendelian inheritance models for CHD. Different inheritance models for CHD for sporadic and familial cases highlighting variable penetrance models associated with different types of mutations.
Figure 3. Disease associated candidate genes along molecular and cellular cascades. Graph outlining an overview of the molecular and cellular cascades harbouring genes that have been linked to cardiac malformations.
Figure 4. From human disease to mouse models for CHD. The identification of a novel locus associated with CHD in families is the first step to understanding disease etiology and is often followed by creating a specific mouse model of disease. Novel genome editing technologies allow for interrogating the functional consequences of mutations in single genes or across genetic networks that drive heart development. The final step is the functional characterisation of gene function and deciphering the tissue or cell‐type specific role of the mutations identified within patients with CHD.
close

References

Andersen TA, Troelsen K, de LL and Larsen LA (2014) Of mice and men: molecular genetics of congenital heart disease. Cellular and Molecular Life Sciences: CMLS 71 (8): 1327–1352. http://doi.org/10.1007/s00018‐013‐1430‐1.

Arrington CB, Bleyl SB, Matsunami N, et al. (2012) Exome analysis of a family with pleiotropic congenital heart disease. Circulation. Cardiovascular Genetics 5 (2): 175–182. http://doi.org/10.1161/CIRCGENETICS.111.961797.

Auman HJ, Coleman H, Riley HE, et al. (2007) Functional modulation of cardiac form through regionally confined cell shape changes. PLoS Biology 5 (3): e53. http://doi.org/10.1371/journal.pbio.0050053.

Blue GM, Kirk EP, Giannoulatou E, et al (2014) Targeted next‐generation sequencing identifies pathogenic variants in familial congenital heart disease. Journal of the American College of Cardiology 64 (23): 2498–2506. http://doi.org/10.1016/j.jacc.2014.09.048.

Bosse K, Hans CP, Zhao N, et al. (2013) Endothelial nitric oxide signaling regulates Notch1 in aortic valve disease. Journal of Molecular and Cellular Cardiology 60: 27–35. http://doi.org/10.1016/j.yjmcc.2013.04.001.

Bruneau BG, Nemer G, Schmitt JP, et al. (2001) A murine model of Holt–Oram syndrome defines roles of the T‐box transcription factor Tbx5 in cardiogenesis and disease. Cell 106 (6): 709–721.

Cripe L, Andelfinger G, Martin LJ, Shooner K and Benson DW (2004) Bicuspid aortic valve is heritable. Journal of the American College of Cardiology 44 (1): 138–143. http://doi.org/10.1016/j.jacc.2004.03.050.

D'Alessandro LCA, Al Turki S, Manickaraj AK, et al. (2016) Exome sequencing identifies rare variants in multiple genes in atrioventricular septal defect. Genetics in Medicine 18 (2): 189–198. http://doi.org/10.1038/gim.2015.60.

Fahed AC, Gelb BD, Seidman JG and Seidman CE (2013) Genetics of congenital heart disease: the glass half empty. Circulation Research 112 (4): 707–720. http://doi.org/10.1161/CIRCRESAHA.112.300853.

Fibison WJ, Budarf M, McDermid H, Greenberg F and Emanuel BS (1990) Molecular studies of DiGeorge syndrome. American Journal of Human Genetics 46 (5): 888–895.

Freeman SB, et al. (1998) Population‐based study of congenital heart defects in Down syndrome. American Journal of Medical Genetics 80 (3): 213–217. http://doi.org/10.1038/nature03940.

Garg V, Muth AN, Ransom JF, et al. (2005) Mutations in NOTCH1 cause aortic valve disease. Nature 437 (7056): 270–274. http://doi.org/10.1038/nature03940.

Hemani G, Knott S, Haley C, et al. (2013) An evolutionary perspective on epistasis and the missing heritability. PLoS Genetics 9 (2): e1003295. http://doi.org/10.1371/journal.pgen.1003295.

Hermisson J and Wagner GP (2004) The population genetic theory of hidden variation and genetic robustness. Genetics 168 (4): 2271–2284.

High FA, Zhang M, Proweller A, et al. (2007) An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation. The Journal of Clinical Investigation 117 (2): 353–363. http://doi.org/10.1172/JCI30070.

Hitz M‐P, Lemieux‐Perreault L‐P, Marshall C, et al (2012) Rare copy number variants contribute to congenital left‐sided heart disease. PLoS Genetics 8 (9): e1002903. http://doi.org/10.1371/journal.pgen.1002903.

Jerome LA and Papaioannou VE (2001) DiGeorge syndrome phenotype in mice mutant for the T‐box gene, Tbx1. Nature Genetics 27 (3): 286–291. http://doi.org/10.1038/85845.

Kerstjens‐Frederikse WS, van de Laar IMBH, Vos YJ, et al. (2016) Cardiovascular malformations caused by NOTCH1 mutations do not keep left: data on 428 probands with left‐sided CHD and their families. Genetics in Medicine: Official Journal of the American College of Medical Genetics 18 (9): 914–923. http://doi.org/10.1038/gim.2015.193.

Kitano H (2004) Biological robustness. Nature Reviews Genetics 5 (11): 826–837. http://doi.org/10.1038/nrg1471.

Korenberg JR, Chen XN, Schipper R, et al (1994) Down syndrome phenotypes: the consequences of chromosomal imbalance. Proceedings of the National Academy of Sciences of the United States of America 91 (11): 4997–5001.

LaHaye S, Corsemeier D, Basu M, et al. (2016) Utilization of whole exome sequencing to identify causative mutations in familial congenital heart disease. Circulation. Cardiovascular Genetics 9 (4): 320–329. DOI: 10.1161/CIRCGENETICS.115.001324. http://doi.org/10.1161/CIRCGENETICS.115.001324.

Li L, Krantz ID, Deng Y, et al. (1997) Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nature Genetics 16 (3): 243–251. http://doi.org/10.1038/ng0797‐243.

Li H, Cherry S, Klinedinst D, et al. (2012) Genetic modifiers predisposing to congenital heart disease in the sensitized Down syndrome population. Circulation. Cardiovascular Genetics 5 (3): 301–308. http://doi.org/10.1161/CIRCGENETICS.111.960872.

Li H, Edie S, Klinedinst D, et al. (2016) Penetrance of congenital heart disease in a mouse model of Down syndrome depends on a trisomic potentiator of a disomic modifier. Genetics 203 (2): 763–770. http://doi.org/10.1534/genetics.116.188045.

Lindsay EA, Botta A, Jurecic V, et al. (1999) Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature 401 (6751): 379–383. http://doi.org/10.1038/43900.

MacArthur DG, Manolio TA, Dimmock DP, et al. (2014) Guidelines for investigating causality of sequence variants in human disease. Nature 508 (7497): 469–476. http://doi.org/10.1038/nature13127.

McBride KL, Marengo L, Canfield M, et al. (2005a) Epidemiology of noncomplex left ventricular outflow tract obstruction malformations (aortic valve stenosis, coarctation of the aorta, hypoplastic left heart syndrome) in Texas, 1999–2001. Birth Defects Research, Part A: Clinical and Molecular Teratology 73 (8): 555–561. http://doi.org/10.1002/bdra.20169.

McBride KL, Pignatelli R, Lewin M, et al. (2005b) Inheritance analysis of congenital left ventricular outflow tract obstruction malformations: Segregation, multiplex relative risk, and heritability. American Journal of Medical Genetics Part A 134A (2): 180–186. http://doi.org/10.1002/ajmg.a.30602.

McCright B, Lozier J and Gridley T (2002) A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development (Cambridge, England) 129 (4): 1075–1082.

McDaniell R, Warthen DM, Sanchez‐Lara PA, et al. (2006) NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. American Journal of Human Genetics 79 (1): 169–173. http://doi.org/10.1086/505332.

Miyake N, Mizuno S, Okamoto N, et al. (2013) KDM6A point mutations cause Kabuki syndrome. Human Mutation 34 (1): 108–110. http://doi.org/10.1002/humu.22229.

Mommersteeg MTM, Yeh ML, Parnavelas JG and Andrews WD (2015) Disrupted Slit‐Robo signalling results in membranous ventricular septum defects and bicuspid aortic valves. Cardiovascular Research 106 (1): 55–66. http://doi.org/10.1093/cvr/cvv040.

Ng SB, Bigham AW, Buckingham KJ, et al. (2010) Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nature Genetics 42 (9): 790–793. http://doi.org/10.1038/ng.646.

Niessen K and Karsan A (2008) Notch signaling in cardiac development. Circulation Research 102 (10): 1169–1181.

Ornoy A and Ergaz Z (2010) Alcohol abuse in pregnant women: effects on the fetus and newborn, mode of action and maternal treatment. International Journal of Environmental Research and Public Health 7 (2): 364–379. http://doi.org/10.3390/ijerph7020364.

Posch MG, Waldmuller S, Müller M, et al and Özcelik C (2011) Cardiac alpha‐myosin (MYH6) is the predominant sarcomeric disease gene for familial atrial septal defects. PLoS One 6 (12): e28872. http://doi.org/10.1371/journal.pone.0028872.

Pradat P, Francannet C, Harris JA and Robert E (2003) The epidemiology of cardiovascular defects, part I: a study based on data from three large registries of congenital malformations. Pediatric Cardiology 24 (3): 195–221. http://doi.org/10.1007/s00246‐002‐9401‐6.

Priest JR, Osoegawa K, Mohammed N, et al. (2016) De novo and rare variants at multiple loci support the oligogenic origins of atrioventricular septal heart defects. PLoS Genetics 12 (4): e1005963. http://doi.org/10.1371/journal.pgen.1005963.

Santos R, Kawauchi S, Jacobs RE, et al. (2016) Conditional creation and rescue of Nipbl‐deficiency in mice reveals multiple determinants of risk for congenital heart defects. PLoS Biology 14 (9): e2000197. http://doi.org/10.1371/journal.pbio.2000197.

Sifrim A, Hitz M‐P, Wilsdon A, et al. (2016) Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nature Genetics 48 (9): 1060–1065. http://doi.org/10.1038/ng.3627.

Silversides CK, Lionel AC, Costain G, et al (2012) Rare copy number variations in adults with Tetralogy of Fallot implicate novel risk gene pathways. PLoS Genetics 8 (8): e1002843. http://doi.org/10.1371/journal.pgen.1002843.

Smemo S, Campos LC, Moskowitz IP, et al. (2012) Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease. Human Molecular Genetics 21 (14): 3255–3263. http://doi.org/10.1093/hmg/dds165.

Southgate L, Machado RD, Snape KM, et al. (2011) Gain‐of‐function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies. American Journal of Human Genetics 88 (5): 574–585. http://doi.org/10.1016/j.ajhg.2011.04.013.

Stittrich A‐B, Lehman A, Bodian DL, et al (2014) Mutations in NOTCH1 cause Adams–Oliver syndrome. American Journal of Human Genetics 95 (3): 275–284. http://doi.org/10.1016/j.ajhg.2014.07.011.

Tandon R and Edwards JE (1973) Cardiac malformations associated with Down's syndrome. Circulation 47 (6): 1349–1355. http://doi.org/10.1161/01.cir.47.6.1349.

Theis JL, Zimmermann MT, Evans JM, et al. (2015) Recessive MYH6 mutations in hypoplastic left heart with reduced ejection fraction. Circulation. Cardiovascular Genetics 8 (4): 564–571. http://doi.org/10.1161/CIRCGENETICS.115.001070.

van der Linde D, Konings EEM, Slager MA, et al. (2011) Birth prevalence of congenital heart disease worldwide: a systematic review and meta‐analysis. Journal of the American College of Cardiology 58 (21): 2241–2247. http://doi.org/10.1016/j.jacc.2011.08.025.

Verdyck P, Holder‐Espinasse M, Hul WV and Wuyts W (2003) Clinical and molecular analysis of nine families with Adams–Oliver syndrome. European Journal of Human Genetics 11 (6): 457–463. http://doi.org/10.1038/sj.ejhg.5200980.

Williams LJ, Correa A and Rasmussen S (2004) Maternal lifestyle factors and risk for ventricular septal defects. Birth Defects Research, Part A: Clinical and Molecular Teratology 70 (2): 59–64. http://doi.org/10.1002/bdra.10145.

Winston JB, Erlich JM, Green CA, et al. (2010) Heterogeneity of genetic modifiers ensures normal cardiac development. Circulation 121 (11): 1313–1321. http://doi.org/10.1161/CIRCULATIONAHA.109.887687.

Zaidi S, Choi M, Wakimoto H, et al. (2013) De novo mutations in histone‐modifying genes in congenital heart disease. Nature 498 (7453): 220–223.

Zetterqvist P (1960) Multiple occurrence of atrial septal defect in a family. Acta Paediatrica 49 (6): 741–747. http://doi.org/10.1111/j.1651‐2227.1960.tb16081.x.

Further Reading

Gelb BD and Chung WK (2014) Complex genetics and the etiology of human congenital heart disease. Cold Spring Harbor Perspectives in Medicine 4 (7): a013953. http://doi.org/10.1101/cshperspect.a013953.

Postma AV, Bezzina CR and Christoffels VM (2016) Genetics of congenital heart disease: the contribution of the noncoding regulatory genome. Journal of Human Genetics 61 (1): 13–19. http://doi.org/10.1038/jhg.2015.98.

Rickert‐Sperling S, Kelly RG and Driscoll DJ (eds) (2016) Congenital Heart Diseases: The Broken Heart – Clinical Features, Human Genetics and Molecular Pathways. Vienna: Springer. http://doi.org/10.1007/978‐3‐7091‐1883‐2.

Rickert‐Sperling S, Kelly RG and Driscoll DJ (eds) (2016) Congenital Heart Diseases: The Broken Heart. Vienna: Springer. http://doi.org/10.1007/978‐3‐7091‐1883‐2.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Preuss, Christoph, Wünnemann, Florian, and Andelfinger, Gregor(Feb 2017) At the Heart of a Complex Disease ‘Molecular Genetics of Congenital Heart Disease’. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026850]