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


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.


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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.

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.

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.‐3‐7091‐1883‐2.

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

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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. [doi: 10.1002/9780470015902.a0026850]