Genetic Evaluation of Cardiomyopathy

HFSA Guideline Approach to Medical Evidence for Genetic Evaluation of Cardiomyopathy

Because genetic testing is relatively new, randomized clinical trials demonstrating that performing the specific genetic test improves outcomes are not available. Thus, we have used a different format for strength of evidence for clinical validity which asks the question "Does the test correlate with the outcome of interest?"8 The hierarchy of types of evidence includes the following:

  • Strength A: The specific genetic test or clinical test has a high correlation with the cardiomyopathic disease of interest in reasonably large studies from multiple centers.
  • Strength B: The specific genetic test or clinical test has a high correlation with the cardiomyopathic disease of interest in small or single center studies.
  • Strength C: The specific genetic test or clinical test correlates with the cardiomyopathic disease of interest in case reports.

The criteria for clinical utility follow those used for overall strength of evidence in the other sections of this guideline (see Section 1), and pose the question, "Does performing the test result in improved patient outcomes?"

  • Strength A: randomized, controlled, clinical trials. May be assigned on the basis of a single methodologically rigorous randomized trial.
  • Strength B: Cohort and case control studies. Post-hoc, subgroup analysis, and meta-analysis. Prospective observational studies or registries.
  • Strength C: Expert Opinion. Observational studies-epidemiologic findings. Safety reporting from large-scale use in practice.

However, as noted previously for clinical validity, randomized or controlled clinical trials or large cohort and case/control studies are seldom available from genetic cardiomyopathy studies. Hence the authors graded strength of evidence based upon the totality of information available.



A careful family history for ? 3 generations is recommended for all patients with cardiomyopathy.

Cardiomyopathy PhenotypeStrength of Evidence
Hypertrophic cardiomyopathy (HCM)A
Dilated cardiomyopathy (DCM)A
Arrhythmic right ventricular dysplasia (ARVD)A
Left ventricular non-compaction (LVNC)A
Restrictive cardiomyopathy (RCM)B
Cardiomyopathies associated with extra-cardiac manifestations (Table 17.4)A


The family history, long established as an essential component of any medical evaluation, is particularly relevant for the cardiomyopathies.9 The first goal of the family history is to ascertain if the cardiomyopathy is familial, and if so, to identify those individuals who may be at risk. Because of reduced penetrance observed in some families with cardiomyopathy, a family history extending to at least 3 generations improves recognition that a cardiomopathy is inherited and helps define dominant or recessive transmission. Patients unprepared for a recitation of their family history may only provide general information suggestive of cardiovascular disease in their relatives. Not uncommonly, the cause of any cardiovascular condition resulting in hospitalization may be described as a 'heart attack,' as is the case with sudden cardiac death (SCD). Hence, when the diagnosis of cardiomyopathy is suggested, the patient should be requested to obtain additional information to confirm or exclude the cardiomyopathy diagnosis. Specific medical information pertinent to the patient's diagnosis should be sought regarding the patient's relatives. For example, in HCM or ARVD/C, targeted questions relating to SCD in teenagers and young adults should be sought. Increasingly, practitioners record a pedigree to illustrate the family history data.

When taking a family history it is imperative that the professional recording it make no a priori assumptions of which side of the family the disease originated9 and should consider bilineal inheritance (transmission of a disease-causing mutation in the same or a different gene from both mother and father). In HCM, reports of large series of patients undergoing comprehensive genetic screening have shown compound or double mutations in 5%.10-12 It has been suggested that some of these individuals may have had more severe disease related to a 'double-dose' effect incurred from the two mutations.12

A second goal, once a cardiomyopathy is suspected or proven to be familial, is to ascertain the inheritance pattern. Pedigree analysis is undertaken to determine if the inheritance is autosomal dominant or recessive, X-linked dominant or recessive, or mitochondrial9 and thus provide an accurate risk assessment. Most genes known to cause cardiomyopathies are transmitted in an autosomal dominant manner. Autosomal dominant inheritance implies that only one copy of the mutation in needed to cause the disease phenotype and that each child has a 50% chance to inherit the mutation. For X-linked inheritance, the mutation is carried in a gene on the X-chromosome.

Expanding a family history beyond the 3rd generation and collecting medical data from relatives known or suspected to manifest clinical disease consistent with the cardiomyopathy in question can be enormously informative. With additional family and clinical data, further analysis of the pedigree may suggest the age of onset, penetrance, lethality, response to treatment and other aspects of the condition. However, because obtaining a family history and related activities outlined above are time and effort intensive, busy practitioners may choose to refer patients with cardiomyopathy to centers expert in genetic cardiomyopathies. Such centers may also provide genetic counseling and genetic testing, compile clinical and genetic databases, and offer research opportunities that are essential for progress in the field.



Clinical screening for cardiomyopathy in asymptomatic first-degree relatives is recommended.

Cardiomyopathy PhenotypeStrength of Evidence
Hypertrophic cardiomyopathy (HCM)A
Dilated cardiomyopathy (DCM)A
Arrhythmic right ventricular dysplasia (ARVD)A
Left ventricular noncompaction (LVNC)B
Restrictive cardiomyopathy (RCM)B
Cardiomyopathies associated with extra-cardiac manifestations (Table 17.4)A

Clinical screening for cardiomyopathy is recommended at intervals (see below) in asymptomatic at-risk relatives who are known to carry the disease-causing mutation(s). (Strength of Evidence = A)


Clinical screening for cardiomyopathy is recommended for asymptomatic at-risk first-degree relatives when genetic testing has not been performed or has not identified a disease-causing mutation. (Strength of Evidence = A)


It is recommended that clinical screening consist of:

  • History (with special attention to heart failure symptoms, arrhythmias, presyncope and syncope)
  • Physical examination (with special attention to the cardiac and skeletal muscle systems)
  • Electrocardiogram
  • Echocardiogram
  • CK-MM (at initial evaluation only)
  • Signal Averaged ECG (SAECG) in ARVD only
  • Holter monitoring in HCM, ARVD
  • Exercise treadmill testing in HCM
  • Magnetic resonance imaging in ARVD (Strength of Evidence = B)

Clinical screening for cardiomyopathy should be considered at the following times and intervals or at any time that signs or symptoms appear:

Cardiomyopathy PhenotypeInterval if genetic testing is negative and/or if clinical family screening is negativeScreening interval if a mutation is presentStrength of Evidence
HypertrophicEvery 3 years until 30 years of age, except yearly during puberty; after 30 years if symptoms developEvery 3 years until 30 years of age, except yearly during puberty; every 5 years thereafterB
DilatedEvery 3-5 years beginning in childhoodYearly in childhood; every 1-3 years in adults.B
ARVDEvery 3-5 years after age 10Yearly after age 10 to 50 years of age.C
LVNCEvery 3 years beginning in childhoodYearly in childhood; every 1-3 years in adults.C
RestrictiveEvery 3-5 years beginning in adulthoodYearly in childhood; every 1-3 years in adults.C

At-risk first-degree relatives with any abnormal clinical screening tests (regardless of genotype) should be considered for repeat clinical screening at one year. (Strength of Evidence = C)


The basis for these extensive clinical screening recommendations (and the counseling and molecular recommendations in the sections that follow) is the fact that cardiomyopathy can be treated in almost all cases, improving survival and/or enhancing quality of life.13,14 In contrast, many other genetic diseases have no useful medical treatment. Further, determining genetic risk of cardiomyopathy prior to disease presentation guides the recommendations for increased surveillance to detect early disease onset and medical intervention. All of these measures may delay disease presentation and progression, thereby avoiding advanced therapies such as cardiac transplantation, or averting the sequelae of life-threatening events, such as sudden cardiac death.14

Most cardiomyopathies are adult onset, and as is common for adult-onset genetic disease, show a variable age of onset and variable penetrance. Hence, clinical screening of first-degree relatives of adults diagnosed with cardiomyopathy is recommended, regardless of whether a disease-causing mutation has been identified in the index patient. Because of the variable age of onset, clinical screening repeated at intervals is recommended, even if clinical genetic testing has not identified a disease-causing mutation in the family. If a disease-causing mutation is identified, the frequency of pre-symptomatic clinical screening in relatives known to be mutation carriers is recommended with increased frequency, as the probability of future disease is increased among carriers. Increased frequency of follow up clinical screening should also be undertaken for at-risk relatives if clinical screening has shown that the disease is familial, even if a mutation has not been found. This is because for genetic cardiomyopathy, familial disease strongly suggests genetic cause. Further, the sensitivity of genetic testing varies greatly (as noted in the background to Recommendation 17.3). Conversely, as the table above shows, if the clinical screening of first-degree relatives is negative, or a disease-causing mutation has not been identified, the intervals for clinical screening are recommended to be less frequent because of the reduced evidence of genetic risk.

The rationale for this latter recommendation, although reasonable, is based upon limited data. With clinical screening, whether the lack of clinical evidence of cardiomyopathy in first-degree family members is helpful to predict the presence or absence of genetic cause of the proband's cardiomyopathy has not yet been resolved. This is because of the variable age of onset and variable penetrance. Resolution of this issue will require data from additional large, rigorously designed clinical and genetic studies. Despite these uncertainties, we suggest that negative molecular genetic findings in the proband and/or no clinical evidence of disease in their family members, integrated with the type of cardiomyopathy, may be helpful to estimate the family members' genetic risk. We emphasize that these risk assessments will vary greatly with the type of cardiomyopathy, because of the varied sensitivity of genetic testing (reviewed in the background to Recommendation 17.3). Thus, we have recommended longer intervals between clinical screenings with less evidence of disease, recognizing that lack of evidence may not necessarily be synonymous with lack of risk. We also acknowledge that while genetic testing is recommended, in some circumstances genetic testing cannot be performed because of a variety of issues (eg, deceased or unavailable proband, funding issues). Hence, the clinician must integrate all data - clinical and genetic - from the patient and his/her family members, to support the clinical decision analysis in genetic cardiomyopathy.

Integration of all of these considerations, most importantly the type of cardiomyopathy, should be taken into account in screening of children, as well, While children can manifest clinical cardiomyopathy, most disease is adolescent- (HCM) or adult-onset. Hence these recommendations should be integrated with the type of cardiomyopathy, the age of onset of other affected members in the pedigree when such data are available, the identity of the cardiomyopathy gene, and other features.

The testing modalities by diagnosis given in Recommendation 17.2 are screening tests to be performed during an initial evaluation of someone of unknown disease status. If any cardiovascular abnormalities are detected, additional testing specific for the cardiomyopathy should be obtained in order to secure a diagnosis and prognosis and to formulate an appropriate treatment plan.

The risks for developing HCM after 50 years of age are reduced but not eliminated15 as are those for ARVD after 50 years of age.16 The utility and role of Holter monitoring and the signal-averaged ECG in the diagnosis of ARVD has been reviewed.16 Magnetic resonance imaging is useful for the diagnosis of ARVD in centers experienced in its use and interpretation for ARVD17; data are not yet available to guide the frequency of its application for screening at-risk family members.

The patient should be encouraged to communicate with at-risk relatives regarding the presenting symptoms of cardiomyopathy, regardless of whether clinical genetic testing is undertaken or, if undertaken, whether the results are positive or negative. They should be counseled to seek medical assistance with symptoms, and in particular be counseled that potentially imminently life-threatening symptoms, such as presyncope or syncope, should be brought to immediate medical attention.

Less evidence is available to support of the genetic basis of RCM than for the other cardiomyopathies, hence its reduced strength of evidence in these recommendations.



Evaluation, genetic counseling, and genetic testing of cardiomyopathy patients are complex processes. Referral to centers expert in genetic evaluation and family-based management should be considered. (Strength of Evidence = B)


The processes involved in clinical and genetic evaluation and testing for cardiomyopathies, integrated with up-to-date genetic counseling, are complex. This is in part because these recommendations are rapidly evolving. Those practicing cardiovascular genetic medicine must remain up to date with the accelerating developments in the field, integrating clinical and genetic evaluations with genetic counseling. This includes knowledge of recent discoveries of mutations in genes not previously implicated in the cardiomyopathies, as well as emerging gene-phenotype and genotype-phenotype correlations. Complexity also results from the extensive locus (many genes) and allelic (many different mutations within those genes) heterogeneity. Advances in genetic testing technology are also leading to a proliferation of new genetic tests for the cardiomyopathies, which are all confounded by this locus and allelic heterogeneity.

This recommendation states that referral to centers expert in genetic evaluation and family-based management should be considered. "Should be considered" language was selected because the strength of the evidence varies with the cardiomyopathy phenotype, the details of the clinical and family information, and other aspects of each situation. Some practitioners with experience in the field may be able to provide appropriate care for cardiomyopathy patients without referral to a geneticist or a cardiomyopathy center with expertise in genetics. In addition to clinical care for the patient's cardiomyopathy, the practitioner will need to select the indicated genetic tests, counsel the patient on the purpose and outcomes of the possible results prior to the collection of blood or other tissue for the test, and then interpret the results to the patient upon receiving test results.18 Whether results are positive or negative, the practitioner also will need to counsel the patient on potential reproductive risks should the patient wish to have children. Referral to genetic counseling services should be considered if these genetic counseling activities exceed the practitioner's skill, interest, or available time.

Several diverse patient situations help clarify this recommendation. The first is that of a cardiomyopathy patient whose parents are deceased and has no siblings or offspring. The primary need for this patient is reproductive counseling; that is, counseling on the risks of transmitting his/her cardiomyopathy to offspring. As presented below, genetic testing is primarily indicated for risk assessment in at-risk relatives, and since this patient has no first-degree relatives, counseling for genetic testing would be directed to reproductive risk assessment.

A second case is that of a patient with restrictive cardiomyopathy with no obvious family history. Since the genetic testing indicated for restrictive cardiomyopathy is much less established than that for HCM or DCM, efforts should be directed to acquiring a complete and comprehensive 3-4 generation family history. While the practitioner needs to understand that the only known genetic basis of familial restrictive cardiomyopathy stems from genes associated with HCM, in most other respects obtaining the family history is similar to that of the other cardiomyopathies.9 A skilled practitioner can accomplish this, but if obtaining a complete and comprehensive family history exceeds the skill, interest or available time, then referral should be considered.

In contrast to RCM, the genetic information, genetic testing and counseling available for HCM is extensive. The professional ordering genetic testing for HCM must be skilled in interpreting the genetic test results and the subsequent counseling based upon the integration of the results (positive or negative), the family history, the clinical data of the patient and any other known affected or unaffected family members. Ideally, the practitioner will also be skilled in the management of the clinical aspects of HCM, integrating the clinical, diagnostic and therapeutic recommendations based on a synthesis of all data.14 This latter point is particularly relevant with HCM because of the complexity of decision analysis for clinical interventions (eg, the assessment of outflow tract obstruction, and if present, selection of a treatment plan that may involve surgical or catheter-based interventions). In most centers expert in providing care for genetic cardiomyopathies, cardiovascular clinicians knowledgeable and skilled in genetics rely on genetic counselors or geneticists to provide comprehensive services.13,14,18 If executing and completing these aspects of management exceed the practitioner's skill, training, interest or available time, then referral to a cardiovascular center specializing in dealing with genetic cardiomyopathy should be considered.

A final example is the question of genetic testing for a familial dilated cardiomyopathy. Even though mutations in >20 genes have been implicated as causative in familial dilated cardiomyopathy (Table 17.2), the role of genetic testing for DCM at this time remains less certain because of the low test sensitivity. Testing recommendations in 17.4 are based in part on the frequency of mutations of certain genes (Table 17.2) and in part on certain phenotypic characteristics of DCM (eg, the almost universal conduction system disease observed in LMNA cardiomyopathy, discussed below). The field is rapidly evolving, and no one simple, comprehensive standard for risk assessment or genetic testing is presently applicable. Referral to a cardiovascular center specializing in genetic cardiomyopathy can assist in defining the appropriateness of genetic testing for DCM patients.

Practitioners may also consider referral to cardiovascular genetics centers to promote the engagement of patients in research. Patient involvement is critical for continued discovery of unknown genes that cause cardiomyopathy, for establishing long-term natural history studies, and for harnessing this information to improve diagnosis and to improve treatments.

The recommendation for genetic counseling for cardiomyopathy follows later (17.6).

Table 17.2: Genetic Causes of Dilated Cardiomyopathy

Gene* Protein OMIM Frequency, familial** Frequency, sporadic** Comments*** References
AUTOSOMAL Dominant FDC Dilated cardiomyopathy phenotype
ACTC cardiac actin 102540 rare rare 50-54
DES desmin 125660 ? ? 53, 55-57
LMNA lamin A/C 150330 7.3% 3.0% 5.5% overall (41/748, 6 studies, see text) 21-26, 58-64
SGCD δ-sarcoglycan 601411 rare rare 56, 65, 66
MYH7 β-myosin heavy chain 160760 6.3% 3.2% 4.8% overall (22/455, 3 studies) 19, 67-69
TNNT2 cardiac troponin T 191045 2.9% 1.6% 2.3% overall (15/644, 3 studies) 19, 67, 69-72
TPM1 α-tropomyosin 191010 rare rare 73
TTN titin 188840 ? ? 74
VCL metavinculin 193065 rare rare 69,75
MYBPC3 myosin-binding protein C 600958 ? ? 68
MLP/CSRP3 muscle LIM protein 600824 rare rare 19,76
ACTN2 α-actinin-2 102573 ? ? 77
PLN phospholamban 172405 rare rare 69, 78, 79
ZASP/LDB3 Cypher/LIM binding domain 3 605906 ? ? 19, 80
MYH6 α-myosin heavy chain 160710 ? ? 45
ABCC9 SUR2A 601439 81
TNNC1 cardiac troponin C 191040 ? ? 72
titin-cap TCAP titin-cap or telethonin 604488 rare rare 19, 46
SCN5A sodium channel 600163 ? ? 2.3% overall (11/469, 2 studies) 82-84
EYA4 eyes-absent 4 603550 ? ? 85
TMPO thymopoietin 188380 ? ? 86
PSEN1/PSEN2 presenilin 1/2 104311 ? ? 87
DMD dystrophin 300377 88, 89
TAZ/G4.5 tafazzin 300394 90, 91
TNNI3 cardiac troponin I 191044 ? ? 92

*Genes are ordered by publication year.
**Rare indicates less than 1%; frequencies are provided only with two or more publications.
***Overall frequencies may include studies that did not distinguish between familial and sporadic cases.

Table 17.4: Cardiomyopathies Associated with Systemic Disease

  • Duchenne Muscular Dystrophy
  • Becker Muscular Dystrophy
  • Emery-Dreifuss Muscular Dystrophy
  • Limb Girdle Muscular Dystrophy
  • Moyotonic Muscular Dystrophy
  • Mitochondrial Myopathy
  • Kearns-Sayre Syndrome
  • Myotubular (Centronuclear) Myopathy
  • Nemaline Myopathy
  • Cytochrome C Oxidase Deficiency
  • Barth Syndrome
  • Danon Disease
  • Fanconi Anemia
  • Diamond-Blackfan Syndrome
  • Sickle Cell Anemia
  • Medium Chain Acyl CoA Dehydrogenase Deficiency (MCAD)
  • Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD)
  • Maroteaux-Lamy Syndrome
  • Fabry Disease
  • Fabry Disease
  • Friedreich's Ataxia
  • Noonan Syndrome
  • Costello Syndrome
  • LEOPARD Syndrome
  • Cardio-Facio-Cutaneous Syndrome
  • Hunter Syndrome
  • Hurler Syndrome
  • Hurler-Scheie Syndrome
  • Maroteaux-Lamy Syndrome
  • I-Cell Disease
  • Pompe Syndrome
  • Beckwith-Wiedemann Syndrome
  • Mitochondrial Myopathy
  • Cytochrome C Oxidase Deficiency
  • Barth Syndrome
  • Danon Disease
  • Down Syndrome
  • Proteus Syndrome
  • Yunis-Varon Syndrome
  • Pallister-Killian Mosaic Syndrome
  • Medium Chain Acyl CoA Dehydrogenase Deficiency (MCAD)
  • Long Chain Acyl CoA Dehydrogenase Deficiency (LCAD)
  • Multiple Sulfatase Deficiency
  • Amyloidosis
  • Sarcoidosis
  • Fabry Disease
  • Endomyocardial Fibrosis
  • Loffler's Eosinophilic Endomyocardial Disease
  • Pseudoxanthoma Elasticum
  • Desmin Myopathy
  • Gaucher Disease
  • Mitochondrial Myopathy
  • Barth Syndrome
  • Naxos Disease
  • Carvajal Syndrome