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Approaching genetic testing in cardiomyopathies

An article from the ESC Council for Cardiology Practice

The availability of genetic testing, which involves direct examination of the DNA molecule, has increased, especially in the last decade with the advent of non-Sanger (non dye-based), next generation sequencing. Here we present its basic principles, and explain in which cases it can be considered in the management of cardiomyopathies. 

Basic Science


Inherited cardiovascular conditions are a heterogeneous group of disorders caused by genetic variants (mutations) with variable disease expression. They include 1) hypertrophic, dilated, restrictive, arrhythmogenic and left ventricular non-compaction cardiomyopathies 2) ion channel diseases - long QT syndrome, short QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, familial atrial fibrillation, and inherited conduction disorders, and 3) aortopathies - Marfan syndrome, Ehlers Danlos syndrome Type 4, Loeys-Dietz syndrome, and familial thoracic aortic aneurysms- as well as familial pulmonary hypertension. 
Most inherited cardiovascular conditions are considered monogenic, where a variant in a single gene is responsible for the disease expression – for example, mutations in the beta myosin heavy chain gene cause hypertrophic cardiomyopathy. In recent years, however, this simple paradigm of “one gene=one disease” has been challenged by the recognition that a proportion of affected patients carry more than one mutation in the same or different genes and that this may affect the clinical expression or severity of the condition. Here, we review the role of genetic testing in cardiomyopathies and the implications for management of patients and training of specialists in cardiovascular conditions (1-4).

When is a gene variant pathogenic?

Determination of the pathogenicity of individual sequence variants can be challenging (5). The first step is to 1) evaluate the frequency of the identified variant in the general population : in more than 1% of the population the genetic variant is defined as a polymorphism. In this case no single allele is regarded as the standard sequence. Instead there are two or more equally acceptable alternatives. The arbitrary cut-off point between a mutation and a polymorphism is 1 per cent. That is, to be classified as a polymorphism, the least common allele must have a frequency of 1 per cent or more in the population. If the frequency is lower that this, the allele is regarded as a mutation. Certain variants are difficult to interpret and are defined as variants of unknown significance. Basic and clinical information regarding the pathogenicity of a given mutation is made up of both clinical information and basic information. 

  1. Clinical information: aims to establish whether or not there is 1) absence in healthy controls 2) cosegregation with the disease in families - i.e., when the genetic variant is found in affected individuals ans not found in unaffected individuals and a 3) previous description of the same mutation (5). 
  2. Basic Information: aims to collect the type of mutation, (frame-shift, nonsense, missense mutations, or ones that affect coding or noncoding regions - exons and introns) the relevance of the protein affected domain, and conservation of the residue in different species and isoforms (phylogenetic conservation). In silico prediction software - i.e refers to the use of computer programmes to predict whether the genetic variant is likely to result in a significant alteration to the function of the gene product- supports this research as well as functional studies (including animal models).

Role of testing

The role of genetic counselling and testing in clinical practice has been addressed in position statements from the Heart Failure Society of America, the European Society of Cardiology and the Canadian Cardiovascular Society (1-4). The ESC guidelines make recommendations to clinicians involved in genetic testing on many levels: regarding 1) information to give during genetic counselling in families with cardiomyopathies, 2) protocol for clinical family screening when genetics is not available, 3) protocol for clinical screening in asymptomatic relatives who carry a disease-causing mutation. They also emit recommendations regarding 1) positive diagnosis (as a complete analysis of potential genes of interest in the proband of a family), 2) predictive diagnosis, 3) prognostic testing, 4) prenatal diagnosis, and appropriate interpretation, and organisation of genetic counselling. 
Practising cardiologists should be proactive in referring patients to specialised inherited cardiovascular conditions or cardiomyopathy clinics for genetic testing, where a multidisciplinary team of physicians, geneticists, genetic counsellors, and laboratory scientists will collaborate in the delivery of the clinical service.

When to test, when not to

In cardiomyopathies, genetic tested is not indicated to:

  • Gain systematic prognostic stratification of a patient with a cardiomyopathy
  • Confirm all clinical diagnoses of cardiomyopathies (6). 
  • Diagnose a borderline or doubtful cardiomyopathy (e.g. differentiation of athlete’s heart and hypertrophic cardiomyopathy) (1).

To date, few correlations between specific genotypes and outcomes have been described and, even in these examples, data are based on small and usually retrospective cohorts with selected mutations.
However, genetic testing can be considered in selected patients or for certain types of cardiomyopathies, after detailed clinical and family assessment (1-4) such as:

  • Identification of a genetic mutation as a diagnostic criterion in arrhythmogenic cardiomyopathy  
  • In the presence of atypical phenotypic features, a correct diagnosis can result in the recommendation of a specific therapy for example enzyme replacement therapy in Anderson-Fabry disease, liver transplantation in transthyretin-related amyloidosis or early prophylactic defibrillator implantation in dilated cardiomyopathy caused by a lamin A/C gene mutation (1).
  • For all patients and families with cardiomyopathies, unless an acquired cause of cardiomyopathy is demonstrated (1-4). 
Furthermore recent research has proven:
  • An association between mutations in the TNNT2 gene and sudden death in patients with hypertrophic cardiomyopathy (7). 
  • That risk of sudden cardiac death in patients with dilated cardiomyopathy is much higher in individuals carrying mutations in the lamin A/C gene.
  • Patients with multiple mutations (especially in hypertrophic cardiomyopathy and arrhythmogenic cardiomyopathy) present with a more severe phenotype.

Other considerations 

Indications from test results for use in diagnosis, prognostic evaluation, and management will vary according to the type of cardiomyopathy because each holds a different diagnostic yield, that is, - a various likelihood that the test will provide the information needed to establish such indications. Indeed, it is not certain that the genetic testing will identify a causative mutation of the gene, even though it might be there. For example, the efficiency of mutation screening is relatively high in hypertrophic cardiomyopathy and arrhythmogenic cardiomyopathy (40-70% and 30-60%, respectively), but is at present significantly lower in dilated cardiomyopathy.
On top of diagnostic yield, other considerations to include before embarking on genetic testing are complexity and cost, impact on outcome and medical management of individuals and their families (8,9). Genetic testing is a complex process, usually undertaken by genetic counselors, clinical geneticists or cardiologists who have received specific training. Communication with the patient and his/her relatives of relevant clinical and genetic information, of which, disease transmission, family risk, clinical and psychological implications, and predictive testing as well as the associated legal and ethical issues is essential. Predictive genetic testing in asymptomatic children poses significant ethical challenges and should only be undertaken by those with specialist training.

Next generation sequencing

Novel technical approaches, such as next generation sequencing, promise to transform clinical practice.  By this genotyping method, it is possible to analyse a very large number of genes simultaneously and even the entire genome quickly and at a reasonable cost. However, the amount of data generated by this method is considerable and this makes the process of interpretation very difficult. A typical study of a patient with cardiomyopathy by traditional Sanger sequencing of 3 – 4 genes may find 5 to 10 non-synonymous genetic variants (i.e. modifying the coding sequence) whereas a targeted next generation study (e.g. 20-40 genes) would find several hundreds of non-synonymous variants. In the future, progressive technical improvements, together with close collaboration between clinicians, basic researchers, and biostatisticians, should help to improve the interpretation of such data. 


With a role in family screening, diagnosis and, management of certain patients with cardiomyopathies, practising cardiologists should be proactive in referring patients to specialised inherited cardiovascular conditions or cardiomyopathy clinics for genetic testing, where a multidisciplinary team of physicians, geneticists, genetic counsellors, and laboratory scientists will collaborate in the delivery of the clinical service.


1)Genetic counselling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.
Charron P, Arad M, Arbustini E, Basso C, Bilinska Z, Elliott P, Helio T, Keren A, McKenna WJ, Monserrat L, Pankuweit S, Perrot A, Rapezzi C, Ristic A, Seggewiss H, van Langen I, Tavazzi L; European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.  Eur Heart J. 2010;31:2715-26
2)Genetic evaluation of cardiomyopathy--a Heart Failure Society of America practice guideline.
Heart Failure Society of America. Hershberger RE, Lindenfeld J, Mestroni L, Seidman CE, Taylor MR, Towbin JA;  J Card Fail. 2009;15:83-97.
3)Guidelines for genetic testing of inherited cardiac disorders.
Cardiac Genetic Diseases Council Writing Group. Heart Lung Circ. 2011; 20:681-7.
4)HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA).
Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ, Ellinor PT, Gollob M, Hamilton R, Hershberger RE, Judge DP, Le Marec H, McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A, Wolpert C, Zipes DP.  Heart Rhythm. 2011;8:1308-39.
5)The interpretation of genetic tests in inherited cardiovascular diseases
Monserrat L, Mazzanti A,Ortiz-Genga M, Barriales-Villa R, Garcia-Giustiniani D, Gimeno-Blanes JR. Cardiogenetics 2011; 1:e8. 
6)A cost-effectiveness model of genetic testing for the evaluation of families with hypertrophic cardiomyopathy. Heart.
Ingles J, McGaughran J, Scuffham PA, Atherton J, Semsarian C.  2012;98:625-30.
7)DNA testing for hypertrophic cardiomyopathy: a cost-effectiveness model.
Wordsworth S, Leal J, Blair E, Legood R, Thomson K, Seller A, Taylor J, Watkins H.  Eur Heart J. 2010;31:926-35.
8)Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria.
Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MG, Daubert JP, Fontaine G, Gear K, Hauer R, Nava A, Picard MH, Protonotarios N, Saffitz JE, Sanborn DM, Steinberg JS, Tandri H, Thiene G, Towbin JA, Tsatsopoulou A, Wichter T, Zareba W. Eur Heart J. 2010;31:806-14.
9)Long-term outcomes in hypertrophic cardiomyopathy caused by mutations in the cardiac troponin T gene
Pasquale F, Syrris P, Kaski JP, Mogensen J, McKenna WJ, Elliott P. Circ Cardiovasc Genet. 2012;5:10-17. 


Vol11 N°2

Notes to editor

Limongelli G, Elliott P, Charron P, Mogensen J, McKeown PP, on behalf of the Genetic Study Group & the Nucleus of the Working Group for Myocardial and Pericardial Diseases.
Co-authors: Alida Caforio, Juan Gimeno-Blanes, Tiina Heliö, Ales Linhart, H, Yigal Pinto, Arsen Ristic, Hubert Seggewiss, and Luigi Tavazzi 

Authors' disclosures: None declared. 
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.