Sporadic dilated cardiomyopathy is often familial

The term cardiomyopathy denotes a myocardial disease. The myocardium is a cellularly heterogeneous structure, with cardiac myocytes comprising about a third of the cells.¹ Cardiomyopathy, in the author’s opinion, is the disease of cardiac myocytes where the primary defect, whether genetic or otherwise, resides. Consequently, myocardial diseases arising from dysfunctions of other cell types, such as cardiac fibroblasts, endothelial cells, and smooth muscle cells, are not considered cardiomyopathies. Similarly, involvement of the myocardium in the altered loading states, such as systemic arterial hypertension or valvular heart disease, and in ischaemic conditions, such as coronary artery disease, is distinct from cardiomyopathies. In these conditions, the primary disorder is not in cardiac myocytes, and involvement of cardiac myocytes is secondary. Nevertheless, it is important to note that the phenotype in cardiomyopathies is the consequence of intertwined, non-linear, and stochastic interactions among multiple cellular constituents of the myocardium as well as the interactions of these cells with the external and environmental factors.

With the above purist definition in mind, whenever the primary defect or insult negatively affects myocyte contractile function, cardiac dilatation, and reduced contractility ensue, which together define dilated cardiomyopathy (DCM). The instigating defect in DCM is typically a mutation (primary DCM) unless DCM is a sequela of treatment with toxic agents, infection, and other secondary causes. In accord with the complexity of the genes and pathways involved in maintaining the proper cardiac structure and function, primary DCM is a genetically heterogeneous disease. Over 100 genes are implicated in the pathogenesis of DCM, albeit evidence for the causal role of several is not conclusive.² Despite the remarkable discoveries during the last three decades, the causal genes in a significant fraction of the DCM cases have remained unknown.

In clinical practice, DCM is commonly encountered as a sporadic disease, whereby there is no known history of DCM in the family members. The familial nature of DCM, however, is often not readily apparent. Unless a family history is carefully extracted, DCM is misclassified as sporadic (Figure 1). The pioneering work of the group at the Mayo Clinic in the 1980s and 1990s illustrated that systematic screening of the relative of the probands with DCM leads to detection of cardiac dilatation and dysfunction, i.e. familial DCM, in ∼20% of the patients.^3,4 Recently Huggins et al. analyzed a large multi-centre data set comprising 1220 probands and detected an overall prevalence of familial DCM in ∼12% of the probands and an estimated prevalence of 30% when all family members were screened.⁵ The study was a cross-sectional multi-centre study and did not benefit from a priori-designed uniform protocol and only a fraction of the family members was examined. Therefore, one might speculate that the prevalence of familial DCM might have been higher if all at-risk family members of probands were systematically evaluated. Likewise, periodic evaluation throughout the years would be expected to identify a higher percentage of familial DCM because of the age dependence of the penetrance. In the study by Huggins et al., the prevalence of familial DCM was somewhat higher in Black than White probands. This might reflect the effects of the modifier genetic variants enhancing the expression of the phenotype. It might also reflect the study population characteristics and the statistical modelling used to estimate the prevalence of familial DCM. The finding should be considered provisional pending testing for replication in independent populations.

Figure 1.

Sporadic DCM changed to familial DCM upon screening of the family members. (A) A case of DCM, which was presumed to be sporadic. (B) A three-generation family of the case was shown in (A). Screening of the family members by history taking, physical examination, obtaining a 12-lead electrocardiogram, performing an echocardiogram, and genetic testing led to the identification of additional family members with DCM. Genetic testing showed co-segregation of the pathogenic variant (PV) with the inheritance of DCM. Symbols: Squares and circles represent males and females, respectively. Full and empty symbols indicate clinically affected and unaffected individuals, respectively. PV indicates a pathogenic variant identified upon genetic testing. The dot inside a symbol identifies a carrier of the PV (without clinical evidence of DCM at the age examined).

Most sporadic cases of DCM have a genetic aetiology and a similar set of genes and mutations are found in familial and sporadic DCM. Shared genetic aetiology suggests that some sporadic cases might indeed be unrecognized familial DCM. Finally, in estimating the prevalence of DCM, it is important to consider the phenocopy conditions as they might mimic sporadic DCM. Examples include DCM due to excess alcohol consumption, treatment with anti-neoplastic agents, infiltrative diseases, and others. Although there is a genetic basis for susceptibility to the phenocopy conditions, they typically are sporadic and do not present as familial DCM.

From the clinical perspective, the existing data emphasize the need for assessing the familial inheritance of DCM (Figure 1). The first step is to construct a pedigree for every proband that is diagnosed with DCM. The clinical evaluation of all at-risk family members, namely the parents, siblings, and offspring of the proband, should include detailed history taking, physical examination, recording of a 12-lead electrocardiogram, and performing complete echocardiography, including tissue Doppler and strain imaging. In some cases, it might be prudent to measure plasma levels of selected biomarkers, such as the B-type natriuretic peptide. Cascade screening of the family member should be performed whenever additional affected members are identified. Moreover, genetic testing is indispensable in the evaluation of the proband with DCM and the immediate family members. The genetic variants identified require extensive analysis to assess their pathogenicity in DCM. Finally, genetic counselling is implemented to inform the proband and the family members.

The yield of genetic testing in identifying the causal pathogenic variant in DCM, however, is low, and ascertaining the causality of the variant(s) in a single individual is exceedingly challenging, if not impossible, for various reasons discussed elsewhere.⁶  In silico prediction algorithms are valuable but insufficient to establish the causal role of a candidate pathogenic variant in DCM. Therefore, it is essential to extend the genetic testing to the at-risk family members and perform exquisite and periodic phenotypic characterization of the family members to assess co-segregation of the candidate pathogenic variant(s) with the phenotype and establish pathogenicity. Physicians are recommended to investigate the familial nature of the DCM whenever they encounter an apparent sporadic case, per the suggested above approach.

Partial elucidation of the genetic basis of DCM in conjunction with the recent technological advances in gene editing and transfer has raised the prospect of correcting the underlying causal mutations in hereditary cardiomyopathies. There have been enormous advances in generating various renditions of the CRISPR system and their applications for genetic manipulations in the in vitro and in vivo systems (reviewed in Musunuru⁷ and Gladka and Baker⁸). Despite the advances, however, the clinical applications of the CRISPR-based systems are limited and are hampered by various technical challenges as well as safety concerns. Currently, the CRISPR-based systems are efficient for targeting the gene of interest for inactivation but are inefficient, promiscuous, and error-prone for allele-specific targeting to correct the underlying causal mutation in single-gene disorders. Likewise, an efficient, cell type-specific, and homogeneous transfer of the gene or base editing material to quiescent cardiac myocytes are challenging. Despite these serious limitations, one might envision clinical applications of the CRISPR-based gene and base editing approaches to certain rare and deadly conditions for which there is currently no effective therapy. Major advances in the CRISPR and gene transfer technologies would be needed for the successful applications of the CRISPR-based systems to correct the causal mutations in patients with hereditary cardiomyopathies.

Funding

A.J.M. is supported in part by grants from NIH, National Heart, Lung, and Blood Institute (NHLBI, R01 HL151737, and 1R01HL132401), and an endowment from The Ewing Halsell Foundation.

Conflicts of interest: None declared.

Authors

Biography: Ali J. Marian, MD, James T. Willerson, M.D. Distinguished Chair in Cardiovascular Research; Professor of Molecular Medicine (Genetics); Professor of Internal Medicine (Cardiology); Director, Center for Cardiovascular Genetics; The Brown Foundation Institute of Molecular Medicine; The University of Texas Health Science Center-Houston, Texas. Dr Marian received his training in clinical cardiology and human molecular genetics at Baylor College of Medicine. He was appointed as a faculty at the Section of Cardiology at Baylor College of Medicine in 1992. He joined the Institute of Molecular Medicine in 2006 to lead the Center for Cardiovascular Genetics. He is recognized for his research achievements in molecular genetics and clinical aspects of cardiomyopathies. He has published over 200 articles in peer-reviewed journals, which collectively have garnered over 11 000 citations. He received the Young Investigator Award from the American College of Cardiology, the Established Investigator Award from the American Heart Association, the Clinician-Scientist Award in Translational Research from Burroughs Wellcome Fund, Distinguished Scientist Award from Baylor St Luke’s Medical Center, and the Best Editor Award from the American Heart Association Circulation Research. He is currently a Deputy Editor for Cardiovascular Research, Section Editor on Genetics for Current Opinion in Cardiology, and the Editor-in-Chief of The Journal of Cardiovascular Aging. He is a former Deputy Editor for Circulation Research, Associate Editor for Circulation and European Journal of Clinical Investigation. His research is supported by R01 grants from the NHLBI-NIH, Leducq Foundation Trans-Atlantic Network of Excellence, and local foundations.