Dilated cardiomyopathy: the complexity of a diverse genetic architecture

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Remarkable progress has been made in understanding the genetic basis of dilated cardiomyopathy (DCM). Rare variants in >30 genes, some also involved in other cardiomyopathies, muscular dystrophy, or syndromic disease, perturb a diverse set of important myocardial proteins to produce a final DCM phenotype. Large, publicly available datasets have provided the opportunity to evaluate previously identified DCM-causing mutations, and to examine the population frequency of sequence variants similar to those that have been observed to cause DCM. The frequency of these variants, whether associated with dilated or hypertrophic cardiomyopathy, is greater than estimates of disease prevalence. This mismatch might be explained by one or more of the following possibilities: that the penetrance of DCM-causing mutations is lower than previously thought, that some variants are noncausal, that DCM prevalence is higher than previously estimated, or that other more-complex genomics underlie DCM. Reassessment of our assumptions about the complexity of the genomic and phenomic architecture of DCM is warranted. Much about the genomic basis of DCM remains to be investigated, which will require comprehensive genomic studies in much larger cohorts of rigorously phenotyped probands and family members than previously examined.

Key Points

  • Point mutations in >30 genes of diverse ontologies, acting via various pathways, are implicated in causing dilated cardiomyopathy (DCM)

  • The prevalence of DCM is likely to have been substantially underestimated, and the condition is likely to be more common than hypertrophic cardiomyopathy

  • The molecular genetics of DCM are characterized by locus and allelic heterogeneity, reduced penetrance, and variable and age-dependent expressivity, with most mutations being rare or even unique ('private')

  • Surveys of large, publicly available exome-sequencing databases suggest an excess of rare variants in known cardiomyopathy-associated genes compared with estimates of disease prevalence

  • The traditional Mendelian paradigm for understanding the genomics of DCM is likely to be incomplete

  • Current sequencing strategies, accumulating clinical evidence, and a molecular genetic-testing sensitivity of 30–40% for DCM provide foundations for the entry of this condition into genomic medicine

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Figure 1: Relationships between genes associated with cardiomyopathies and related phenotypes.
Figure 2: A remarkably heterogeneous set of rare genetic variants yields a single DCM phenotype.
Figure 3: Network of DCM-associated gene–gene interactions from the STRING database.
Figure 4: Morphology of the cardiomyopathies.
Figure 5: Pedigree analysis.
Figure 6: Penetrance and variable expressivity of LMNA-associated DCM.
Figure 7: Allelic heterogeneity shown by DCM and HCM mutations in TNNT2, which encodes cardiac troponin T.130
Figure 8: Variations on the Mendelian disease paradigm relevant to DCM genetics.
Figure 9: Future areas of research in dilated cardiomyopathy.


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This work was supported by NIH award HL58626 (R. E. Hershberger).

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All the authors contributed substantially to researching and writing this manuscript, and to reviewing/editing it before submission.

Correspondence to Ray E. Hershberger.

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