Journal of the Practice of Cardiovascular Sciences

: 2015  |  Volume : 1  |  Issue : 2  |  Page : 120--127

Clinical genetic aspects of cardiomyopathies

Mitali Kapoor1, Sandeep Seth2, Vadlamudi Raghavendra Rao1,  
1 Department of Anthropology, Laboratory of Biochemical and Molecular Anthropology, University of Delhi, New Delhi, India
2 Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India

Correspondence Address:
Prof. Vadlamudi Raghavendra Rao
Department of Anthropology, Laboratory of Biochemical and Molecular Anthropology, University of Delhi, New Delhi - 110 007


Cardiomyopathies are a major cause of heart disease. Not only the patients, but also their families are severely burdened by these illnesses. In the past decade, studies revealed the heterogeneity of these diseases in terms of clinical presentation, as well as their genetics. Studies done in the last few decades revealed a new concept of complex manifestation of cardiomyopathies with different heterogeneity level, penetration, and inheritance. The incomplete penetrance, genetic heterogeneity, and variable expression in cardiomyopathies paradoxically raise hopes that the development of novel disease modifying therapies may be achievable.

How to cite this article:
Kapoor M, Seth S, Rao VR. Clinical genetic aspects of cardiomyopathies.J Pract Cardiovasc Sci 2015;1:120-127

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Kapoor M, Seth S, Rao VR. Clinical genetic aspects of cardiomyopathies. J Pract Cardiovasc Sci [serial online] 2015 [cited 2020 May 30 ];1:120-127
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Cardiomyopathies are a heterogeneous group of disorders, with functional and structural myocardial abnormalities.[1] Recently, various classifications came into light depending on the clinical as well genetics basis, which provide enhanced tools for cardiologists to describe the patients and their family members affected with different types of cardiomyopathies. In 2006, the American Heart Association classified the cardiomyopathies into primary cardiomyopathies which primarily affect the heart alone and secondary cardiomyopathies which are a result of other systematic illness affecting many other parts of the body. These groups were again subgrouped into another two broad categories, that is, genetic and molecular types.[2] However, with growing understanding of genetics by modern laboratories, new overlap genetics among different cardiomyopathies came into light. The European Society of Cardiology subgrouped the cardiomyopathy into familial or genetic, and nonfamilial or nongenetic forms.[3] However, the new MOGES classification, considers every aspect, that is, morphological, organ in which disease is associated, genetic or familial inheritance, etiology which explains the underlying cause, and the heart failure stage of a patient.[4]

In the last two decades, the family screening has contributed to improving the evaluation of familial cardiomyopathies, which has allowed the identification of family members who are predisposed the development of disease based on the inheritance pattern. Most cardiomyopathies show different types of inheritance patterns, in which comprehensive assessment of family history plays an important role.[5],[6],[7] For early clinical evaluation, the electrocardiography and echocardiography can prove to be helpful. However, clinical and genetic studies reveal the clinical and genetic heterogeneous nature of cardiomyopathies.[7],[8],[9],[10],[11],[12]

 Genetics of Cardiomyopathy: The Basis and the Methods

[Figure 1] shows the steps involved in the evaluation of patients of cardiomyopathy for a genetic etiology and it consists of clinical screening of the entire family for three generations, as well as looking for any known or unknown mutations in the patient. If a mutation(known [pathogenic]) or unknown [called a variant of unknown significance] is found, then the next step is to look for the pathogenic mutations in the rest of the family members. The significance of the unknown mutations is assessed before it is used for testing. These aspects of testing are discussed further in this article.{Figure 1}

 Pedigree Analysis (Family Screening)

The pedigree analysis in the clinical research plays an important role to access or trail several generations of a family for specific characteristics. It provides a systematic illustration with significant phenotypic features extending through numerous generations. A family involved in pedigree usually includes at least three generations. Squares represent males and circles represent females in the pedigree tree. The shape is darkened when the trait is present in an individual. Pedigree analysis can figure out that trait running through the family, whether it is recessive, dominant, or X linked. In many traits, the mode of inheritance is already very well understood such as blood groups and color blindness, whereas there are evidences for other traits in which mode of inheritance is still unknown such as in heart diseases, breast cancer, and diabetes. Hence, pedigree analysis helps a lot to identify accurately the mode of inheritance among different cardiomyopathy patients [Figure 2]. It provides information about marriage patterns among the family, that is, whether they belong to exogamous or endogamous societies. Exogamy and endogamy refer to getting married to someone from outside and inside one's immediate social group, respectively. The two words also refer to the biological phenomenon of outbreeding or inbreeding. In the Indian society, as of now, 95% marriages take place within endogamous groups such as caste/subcaste and tribe/subtribe. Many diseases are present, particularly among the endogamous group due to consanguineous marriages and increasing homozygosity in communities and increasing susceptibility to genetic diseases. Pedigrees help us to detect any other disease or common syndrome, which could help to understand the total family profile and help in therapeutic interventions.{Figure 2}


After analyzing the pedigree of the patient, the mode of inheritance can be summarized between the affected and unaffected family members. There are different modes of transmission leading to autosomal dominant (AD), autosomal recessive (AR), and X linked mode of inheritance.[13],[14],[15],[16],[17],[18],[19] In the AD mode of inheritance, there is a 50% probability of offspring, inheriting the single disease allele which is sufficient to cause the disease phenotype. In AR mode, there is only 25% of chance for each offspring that will inherit the disease allele from both parents, and two copies of mutant alleles are required to express the phenotype. In X linked inheritance, only one copy of the allele on the X chromosome is required for an individual to be susceptible for an X linked dominant disease. It can affect both sexes, although males are more severely affected because of a single X chromosome. [Figure 2] depicts these three types of inheritance patterns. Dilated cardiomyopathy (DCM) has witnessed different patterns in familial forms, including AD and recessive, X linked and maternal, that is, mitochondrial inheritance has also found, however, the AD forms represent the most.[20] In hypertrophic cardiomyopathy (HCM) as well, AD inheritance pattern is seen commonly.[21],[22],[23]

 Genetic Testing in Cardiomyopathies

Genetic testing or DNA testing, allows the genetic diagnosis of vulnerabilities to inherited diseases. In addition to study chromosomes to the level of individual genes, genetic testing includes tests for the presence of genetic diseases, or mutant forms of genes associated with increased risk of developing genetic disorders. Genetic testing identifies changes in chromosomes, genes, or proteins. Genetic testing is usually considered, when an individual has a positive family history. The molecular genetic study basically requires DNA, which is isolated from blood samples collected from clinically affected patients. The preliminary genetic testing starts with the analysis of known genes, previously reported as candidate genes [Figure 3]. One of the methods to look for mutations is denaturing high performance liquid chromatography (DHPLC) which is a method of chromatography for the detection of base substitutions, small deletions, or insertions at the DNA. Thanks to its speed and high resolution, this method is particularly useful for finding polymorphisms in DNA. The other method is Sanger sequencing, which is a method of DNA sequencing based on the selective incorporation of the chain, terminating dideoxynucleotides by DNA polymerase during in vitro DNA replication. Developed by Frederick Sanger in 1977, it was the most widely used sequencing method for approximately 25 years. More recently, it has been supplanted by “Next Gen” sequencing methods, especially for large scale, automated genome analyses. However, the Sanger method remains in wide use, for smaller scale projects and validation of Next Gen results.{Figure 3}

Candidate genes are screened directly using Sanger sequencing and indirectly by DHPLC methods of variants in exons (coding region of DNA) and intron (noncoding region of DNA) boundaries.[24],[25],[26],[27],[28],[29],[30] In some cardiomyopathies, genes which are strongly associated can be focused on such as in HCM, where 30–45% of genetic cases are known to be caused by mutation in MYH7 and MYBPC3 genes [Table 1].[23] Till date, nearly 1500 mutations have been associated with HCM, while 200 mutations are involved with gene MYH7;[30],[31] therefore in such cases, a candidate gene approach is constructive and cost-effective. Candidate genes reported to be associated with disease phenotypes are advantageous to form candidate gene panels which are available to screen mutations. However, efforts for the last three decades to identify the causative genes associated with cardiomyopathy, identified mutations in ~60% of cardiomyopathy cases only.[32]{Table 1}

Cardiomyopathies were previously considered to be a monogenic disease that means mutation in a single gene can be responsible for the disease. However, genetic studies in the last two decades revealed the polygenic feature of cardiomyopathies. Technological advancement in sequencing techniques such as next generation sequencing (NGS) provides the platform that can explore a very large number of genes concurrently at a reasonable cost. It is now possible to sequence the whole exome, that is, the whole coding region of DNA to identify causal variation or whole genome where total DNA sequence, that is, both exonic and intronic regions can be sequenced. This approach helps in the discovery of new candidate genes and private mutations prevailing in families. Private mutations are rare or novel gene mutations usually found in single families, causing disease and not previously reported.

 Pathogenicity of Mutations

The genetic code other than that normal is referred to as a mutation or “variant.” Mutations identified through the genetic analysis are tested bioinformatically to predict pathogenicity. To predict the pathogenicity or functional significance of variants identified is a difficult task and challenging. The first step in the process of pathogenicity prediction is to differentiate between mutation and polymorphism on the basis of rarity. Variants are known to be polymorphic if the frequency variation is more than 1% in the general population. If the frequency of an allele is <1% variation, it is considered as a mutation. Most of the known variation in the sequence is single nucleotide substitutions accounting for approximately two-third of the mutations.[33] Single nucleotide mutation present in the coding region (exon) can be synonymous or nonsynonymous. Synonymous mutation is known as silent mutation where the formation of new codon due to substitution codes the same amino acid, whereas nonsynonymous mutation is where the codon encodes a different amino acid. The missense mutation is the most prevalent form of nonsynonymous mutation in cardiomyopathies, which replaces the wild amino acid with a different one. However, functional consequences may depend on the biochemical and structural properties of amino acid that is, substituted in the location in the protein.

 Genes Involved in Genetics of Cardiomyopathies

Genetic studies in the last decade had revealed several possible candidate genes involved in the pathogenesis of cardiomyopathies. Genes that are involved in pathogenesis show different disease phenotypes and can be categorized according to the functional consequences of mutation such as sarcomeric protein mutations, intermediate filament and dystrophin associated glycoprotein mutations, intercalated and z disc mutations, lamin A/C mutations, and desmosome protein mutations. Sarcomeric proteins are the main components of cardiac myocytes and mutation in genes encoding sarcomeric proteins are known to cause HCM, DCM, restrictive cardiomyopathy (RCM), or arrhythmogenic right ventricular cardiomyopathy (ARVC). Till date, more than 400 mutations in gene encoding b-cardiac myosin heavy chain (MYH7) have been found.[34] Intercalated filament and dystrophin associated glycoprotein mutations also play an important role as it is a linking protein between the Z disc and sarcolemma. DCM has been associated with mutations in these proteins. Animal model studies as well cleaved dystrophin, show DCM features and heart failure.[35] Intercalated disc are connections between cardiac muscle cell which enable the transmission of electrical impulses through the network, while z disc anchors actin, titin, and nebulette filaments. Mutations in these sections of the cardiac muscle cause HCM [36],[37] and lead to heart failure. Lamin A/C protein is an inner nuclear membrane protein which contains emerin and lamin A/C. Lamin A/C and emerin mutations are known to be associated with DCM only rather than RCM, HCM, or ARVC.[38],[39] Desmosome proteins works as an adhesive material between cell to cell connection, which resist shearing forces. Desmosome provides functional and structural connections and contains different components, such as plakoglobin, desmoplakin, plakophilin 2, and cardiac ryanodine receptor 2. ARVC is an exceptional cardiomyopathy which is caused by mutations in desmosome proteins.[40],[41],[42],[43],[44]

 What we Understood from Genetic Studies so Far?

Genetic studies done till date represent the different aspects of the genetics of cardiomyopathies that show a different scenario to explain the manifestation of disease. These genetic aspects include different penetrance, variable expressivity of phenotypes, genetic heterogeneity, phenocopies, and phenotype genotype correlation among the patients of cardiomyopathies [Figure 4].{Figure 4}


Penetrance has different aspects such as complete and incomplete. Penetrance is known to be complete when all the individuals carrying mutations develop the disease, whereas incomplete when individuals carrying mutations never develop a disease phenotype. Cardiomyopathies showed a great degree of incomplete penetrance in many reports. ARVC with an AD and recessive pattern of inheritance shows complete penetrance.[45],[46],[47],[48],[49] HCM represents a different degree of penetrance in which 69% show incomplete penetrance, 55% show age-related penetrance, and penetrance is found to be greater in males than females.[47] Familial DCM can also have asymptomatic individuals in a family showing age-related penetrance, particularly seen in an AD pattern of inheritance.[46]

Variable expressivity

Variable expressivity is a trait where the same genotype expresses variable expression of disease such as the age of onset, degree of severity in individuals, and even among the members of the same family carrying the same mutation. Inherited cardiomyopathies usually show variable expression, such as cardiac hypertrophy ranges from mild to severe in patients with HCM.[50],[51] There are cases of intrafamilial reports of variable expression of the same allele. In DCM, familial probands show variable expression from sporadic cases in terms of age of onset, severity of disease, and New York Heart Association classification.[52],[53] Partially, these types of variable expressivity are usually explained by modifier mutations present in the same chromosome or different chromosomes or by environmental effects.

Genetic heterogeneity

Genetic heterogeneity can be explained as same phenotype present in different genotypes. In HCM, 22 different loci have been mapped till date and more than 250 mutations in the MYH7 gene have been reported.[51] Different genes causing the same disease makes the disease more complex in terms of pathology mechanism.[46] The rarest cardiomyopathy, that is, RCM also represents this feature. Till date, all eight sarcomeric genes are reported to be associated with RCM.[54] In fact, in dilated cardiomyopathy, till date more than 40 genes have been known to be associated. Such different mutations in the same genes or in different genes causing the same phenotypes represent the genetic heterogeneity among cardiomyopathies.


Phenocopies are other disease conditions where the phenotype is same but has different causes. Similar phenotypes in different disease can be clinically significant and may inherent in different patterns, or may have different responses to drug therapies because of different disease manifestation and the pathophysiological mechanisms.[55] In cardiomyopathies, this phenomenon is most commonly seen in HCM where there are many phenocopies of HCM, and on echocardiography it is often misdiagnosed with other diseases. Cardiac hypertrophy is the main clinical phenotype in different diseases, and therefore, called as HCM phenocopies. Six percent of affected Fabry's disease are known to show HCM phenocopy and is often misdiagnosed with HCM.[56] Sometimes, this phenotype has also been misdiagnosed with RCM.

Phenotype genotype correlation

Phenotype genotype correlation is an interaction between the genetic variations and phenotype presented. Cardiovascular disease, especially cardiomyopathies, such as HCM and DCM can be caused by specific mutations in same sarcomeric genes which show phenotype genotype correlation. RCM and HCM are found to be overlapping in genetic makeup but have a different phenotype, sometimes overlapping phenotype as well. A study reported a mutation p. Arg192His in an adolescent girl with HCM, while the relative carrying the same mutation had RCM.[57] Such studies indicate the differences in biophysical consequences of the mutations. However, the variation among the phenotypic expressions of disease within the family members denies the strong genotype phenotype correlation. For example, HCM caused by Glu101Lys in the ACTC1 gene showed a consistent relation with an apical form in only minority of cases.[58] However, there is susceptibility to conduction disease in DCM caused by LMNA gene mutations warranting the need of pacemaker or implantable cardioverter-defibrillator.[59],[60] In such complex disease, complexity also increases due to the presence of two or more variants in same or another chromosome as double or compound heterozygotes [54],[61],[62],[63],[64] and presence of such heterozygotes complicates the situation about which mutation acts like a driver mutation and which one act as a modifier. To understand such complexities, long term studies are required to gather consistent evidence.[55]

 Modifier Genes and Environmental Effects

Features such as penetrance, variable expressivity, and phenotype genotype heterogeneity reveal a different story about the genetic makeup of cardiac phenotypes. Thus, despite the initial enthusiasm for the genetic studies in cardiology and the risk demonstration of disease, it is apparent that no particular mutation has any specific clinical manifestation. Thus, the same mutation causing different disease phenotype explains the role of other genes (modifier genes) and environmental effect on disease manifestation. Genetic factors other than the causal mutations are referred to as the modifier genes that can modify the disease penetrance. Although it is thought that cardiomyopathies are monogenic disorder, the studies from the last two decades show the complex nature of disease in which modifier genes have its role. The final disease manifestation is, therefore, a result of causal mutation, variations in modifier genes, and environmental effects.[65] The human genome comprises 25,000–30,000 genes which contain 2.1 million single nucleotide polymorphism (SNP), out of which one lakh mutations are likely to affect expression levels or structural component of encoding genes. Many studies reveal that such SNPs are associated with final disease outcome such as angiotensin 1 converting enzyme 1 is known to be associated with severity in HCM phenotypes by many studies.[65],[66],[67] There are many other environmental modifiers that play an important role in the final manifestation of disease; such factors include diet, fitness, and psychological stress. These factors are well recognized as an impact on the outcomes with cardiac disease.[68],[69],[70],[71] Psychological stress has been found to be a trigger of ventricular events, among the HCM patients [71] and mental stress may have an impact on the development of ventricular arrhythmias in ARVC.[72] Training in sports is known to be reported in patients with increased risk of progression of the disease. There is 5.4 fold higher risk of sudden cardiac death among competitive athletes than nonathletes in ARVC patients.[73],[74]

 Cardiomyopathies in India

The picture elucidating the cardiomyopathy in India has not been that much clear till date. Only a few attempts have been made to evaluate the genetics behind the cardiomyopathy of Indian patients [Table 2]. The first attempt to check the genetics behind HCM was done by Tanjore et al. in 2006.[75] In this study, only few exons of MYBPC3 gene were screened, and two mutations were reported to be associated with HCM.[76] In RCM, there is a study with 10 RCM patients. In this study, the association of TNN13 gene and MYH7 gene mutations was found as causing a more severe phenotype.[76]{Table 2}

 Future Prospects

In the last five decades, understanding of the cardiomyopathies has increased many folds, opening an era for genetic testing on the clinical front. In silico analysis, as well emerged as a tool to classify the variants in this era of NGS.[88] However, further research is still required to identify the pathophysiological mechanism leading to such complex phenotypes with phenotype and genotype heterogeneity. The new coming era of technology-driven research should explore new insights such as (1) the complete mapping of genes to understand the genetics of cardiomyopathies with the advent of new cost-effective technology, that is, NGS. (2) To understand the pathophysiological mechanism of disease leading to the new interventions such as personalized medicine or pharmacogenomics.

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Conflicts of interest

There are no conflicts of interest.


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