Molecular Genetics of Dilated Cardiomyopathy


Dilated cardiomyopathy (DCM) is an autosomal dominant disease characterised by dilation of the left ventricle and reduced systolic function. Although hundreds of mutations in more than 40 genes have been attributed to DCM, affecting a wide variety of structural proteins, conduction pathways and contraction mechanisms, this accounts for approximately 40% of familial genetic causes. Additionally, due to low prevalence of any particular single gene mutation in the population, as well as genetic overlap with other cardiomyopathies and diagnostic technology limitations, the diagnosis of DCM remains difficult. The introduction of high‐throughput deoxyribonucleic acid (DNA) sequencing through multigene testing panels has improved diagnostic sensitivity. Furthermore, functional studies have provided innovative approaches to advance collective understanding of DCM aetiology, pathogenesis and diagnosis.

Key Concepts:

  • DCM is an autosomal dominant disease affecting 1 in 2500 individuals with up to 50% of cases attributed to genetic causes.

  • Approximately 40 genes have been discovered as part of DCM aetiology, but this accounts for only 40% of genetic cases.

  • Mutations causing DCM have been discovered in multiple cardiomyocyte proteins and pathways, with most mutations representing a rare cause of DCM and each contributing a low frequency of DCM cases.

  • Mutated genes involved in DCM include those encoding sarcomeric, cytoskeleton, nuclear membrane and ion channel proteins; most mutations leads to a similar DCM phenotype.

  • DCM‐associated rare gene variants found both in research and clinical settings require confirmatory and follow‐up studies, because some of them may eventually result in benign common variations.

  • Functional studies model systems and animal models, such as in zebrafish, are useful for clearly observing the heart, and these studies have been successful in demonstrating distinct cardiac phenotypes for DCM‐related gene mutations.

Keywords: dilated cardiomyopathy; cardiovascular disease; cardiomyopathy; zebrafish; next‐generation sequencing; autosomal dominant disease; allelic heterogeneity; cardiomyocyte

Figure 1.

Cardiomyopathy genes: overlap and genetic heterogeneity. Mutations in a large number of genes can cause cardiomyopathy, as well as mutations within the same gene may cause different phenotypes. For instance, the gene LMNA can cause DCM and left ventricular noncompaction (LVNC), and the TTN gene can cause a variety of different forms of cardiomyopathies. Reproduced with permission from Sinagra et al. (2013). © Springer Science and Business Media.

Figure 2.

Components of the cardiomyocyte and known disease genes. In this illustration of the cardiomyocyte, the extracellular matrix, sarcolemma, sarcomere and nucleus are shown along with a variety of interactive proteins: mutations and consequent altered function of any of these interacting proteins can result in dysfunction and a clinical cardiac phenotype such as DCM. Reproduced with permission from Towbin and Lorts (). © Elsevier.

Figure 3.

A zebrafish model of DCM. (a) Images of lateral views of 72 h old zebrafish embryos injected either with Morpholino (MO)‐control or MO‐sarc, an antisense oligonucleotide that suppress the expression of the target gene δ‐sarcoglycan. (b) Zoomed views of their hearts, showing a DCM phenotype in the MO‐sarc treated embryo, with significant pericardial oedema. (c) Decrease in ventricular contractility in the DCM zebrafish model. Reproduced with permission from Vogel et al. (). © Elsevier.



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Further Reading

Bagnall RD, Ingles J and Semsarian C (2011) Molecular diagnostics of cardiomyopathies: the future is here. Circulation: Cardiovascular Genetics 4: 103–104.

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Roberts R, Marian AJ, Dandona S and Stewart AFR (2013) Genomics in cardiovascular disease. Journal of the American College of Cardiology 61(20): 2029–2037.

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Mestroni, Luisa, Tharp, Charles A, Sweet, Mary E, Graw, Sharon L, and Taylor, Matthew RG(Jun 2014) Molecular Genetics of Dilated Cardiomyopathy. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024317]