Health Care Professionals & Scientists

Information on DCM, FDC, and Referring Patients to the Research Project

Professionals

 

Referring Patients for Research

Referring Patients for Research

guidelines and instructions for referring patients and families to us for research purposes

Background on DCM

Background on DCM

introduction to dilated cardiomyopathy for clinical and research professionals 

The Genetics of DCM

The Genetics of DCM

brief overview of the genetics of dilated cardiomyopathy

Clinical Recommendations

Clinical Recommendations

screening, diagnosis, counseling and treatment recommendations for patients with IDC  and patients & families with FDC

Review of Genetic DCM Research

Review of Genetic DCM Research

key references for genetic dilated cardiomyopathy research and a table displaying the genes implicated in cause of DCM

Genetic Evaluation of Cardiomyopathy

Genetic Evaluation of Cardiomyopathy

Genetic Evaluation of Cardiomyopathy: A Heart Failure Society of America Practice Guideline 

This page provides information most commonly sought by health care professionals and scientists regarding dilated cardiomyopathy (DCM) and familial dilated cardiomyopathy (FDC). Please refer your patients and their family members who are willing and interested to participate in this research project.

We hope you find this information useful. If you have questions that have not been addressed here, please contact us. We are updating and improving this website continuously. We have not been able to include all of the literature in this rapidly expanding field, and we apologize to our many colleagues if we did not integrate your reports into this website.

 

 

Referring Patients for Research Purposes

Please consider referring your patients with idiopathic dilated cardiomyopathy (IDC) and their family members (with or without DCM) to us for research purposes. The most important aspect of our success is your patient’s enthusiasm and willingness, and that of their family members, to participate in our research.

 

We accept individuals with DCM whether familial or non-familial, however we always emphasize enrollment of first degree relatives (parents, siblings, and children). Once an individual with IDC (confirmed by medical records) enrolls in our study, we invite first-degree relatives (with and without heart disease) to participate.  Reported unaffected family members should undergo clinical cardiovascular screening. All relatives who are reported to have IDC are also invited to participate, regardless of their degree of relationship. Reported affected family members should provide medical records confirming their diagnosis. We accept families of any size.

Some patients may have already undergone clinical genetic testing of a DCM gene panel by a commercial laboratory, and they are welcome to enroll. We would especially encourage referral if the testing results were negative, since this could be an opportunity for discovery. Families with negative test results who have multiple affected family members available and willing to participate are particularly of high value for discovery studies. Please refer them.

If your patient is near to a DCM Consortium site, with your consent we will consider referring them to that site for participation in our currently funded Precision Medicine study.

If your patient is ineligible for the Precision Medicine study, we are able to enroll patients (at this time in 2017 and 2018) to the pilot phase of the Discovery study via telephone, mail and email. Please contact us by email or phone for additional information regarding enrollment of your patients to the Discovery or Precision Medicine studies.

We will need the following information from you or your office:

1) Assurance that your patient has agreed that they may be contacted to discuss participation in our research program, and

2) Their contact information (name, and phone number or email address).

Patients can also initiate contact if so they wish. We will do the rest.

After establishing contact with your patient, we will:

  • Discuss the genetics of DCM
  • Discuss indication for screening of family members and clinical genetic testing
  • Inform them about our research program and the Discovery and Precision Medicine studies, and identify options available to them
  • If for enrollment to the Precision Medicine Study at a Consortium site other than OSU, facilitate a referral (the same steps shown below will be conducted at the Consortium site)
  • If for enrollment to the Precision Medicine study at OSU, request to see the patient in person for research participation
  • If for enrollment to the Discovery study by OSU, OSU will send an enrollment kit to the patient (which contains informed consent documents, blood tubes, instructions, and a prepaid UPS return mailer)
  • Request their written informed consent
  • Obtain a 3-4 generation family history
  • Seek a release of medical information
  • Request copies of their pertinent cardiovascular medical records

Once your patient enrolls, we will discuss participation of their family members. We obtain verbal consent for contact of their family members to offer them participation in the study. Family members may also initiate contact if so they wish.

If a family is very large, with multiple affected members living in the same geographical area, we may consider travelling to screen the entire kindred by exam, ECG and echocardiography.

At time of writing (Fall 2017) we cannot guarantee when, or even if, a patient’s DNA will be sequenced for research purposes in the Discovery study, based upon the availability of research funding or other resources for this purpose. (We clarify that this does NOT apply to families enrolled in the funded Precision Medicine study). However, we do consent patients for return of genetic results, and we do make available the return of relevant results (using CLIA-compliant approaches) to research subjects as they become available.

 

 

Background on DCM

What is dilated cardiomyopathy?
Dilated cardiomyopathy is a descriptive term that refers to heart muscle disease where the left ventricle dilates, or enlarges, and has reduced systolic (pumping) function. Thus, the key diagnostic features of dilated cardiomyopathy are left ventricular enlargement (LVE) with decreased systolic function.
What are the causes of dilated cardiomyopathy?
In the adult population approximately 50-60% of DCM is caused by ischemic cardiomyopathy. Ischemic cardiomyopathy results from loss of myocardium from myocardial infarction (heart attack), which may lead to a myopathy in the remaining heart muscle. Approximately 40-50% of dilated cardiomyopathy in adults is idiopathic dilated cardiomyopathy (IDC). In children idiopathic dilated cardiomyopathy accounts for approximately 2/3 of cases. By definition, the etiology of IDC is unknown. Other identifiable causes of cardiomyopathy include, among others:

  • Valvular cardiomyopathy(from volume or pressure overload, e.g., mitral regurgitation or aortic stenosis, respectively)
  • Toxic cardiomyopathy, most commonly from chemotherapeutic agents such as anthracycline antibiotics
  • Rheumatic heart disease
  • Infiltrative cardiomyopathies, such as hemochromatosis or amyloid, although these also commonly present as non-dilated cardiomyopathy
  • Inflammatory cardiomyopathies, such as sarcoid or those associated with collagen vascular disease, or other conditions associated with inflammation that rarely present in association with cardiomyopathy (systemic lupus erythematosus, Kawasaki disease, Churg-Strauss disease, eosinophilic myocarditis, etc).
  • Infectious, e.g., Chagas disease

An IDC diagnosis is based upon finding reduced ventricular function in the setting of left ventricular dilatation, with other causes of cardiomyopathy excluded. We define significant coronary artery disease as > 50% obstruction of a major epicardial coronary artery.  Because the term IDC was coined before evidence of a genetic basis became available, it is now known that some IDC cases are caused by pathogenic rare genetic variants in more than 30 genes. Individuals with IDC should therefore undergo a genetic evaluation, as recommended by the Heart Failure Society of America Guideline for the Genetic Evaluation of Cardiomyopathy (2009).

What is familial dilated cardiomyopathy, and what are the diagnostic criteria for FDC?
The usual diagnostic criteria for FDC is an index patient with a formal diagnosis of IDC, and who has at least one first, second, or third degree relative who has also met the diagnostic criteria for IDC. The term FDC is based on clinical grounds; it is not dependent on knowledge of a specific genetic cause.
Are there any key findings in FDC?
No, there are no singular or key findings that would help to distinguish a patient with simplex IDC from a patient with FDC.

Families with multiple affected relatives often display a combination of mild and severe disease across all generations. Within the same family, DCM may be manifest as subtle clinical symptoms or mild arrhythmias, but also may exhibit sudden death or dilated cardiomyopathy leading to heart failure and/or heart transplantation. We have also found that some families may have a predisposition to a pattern of presentation. Such patterns include similar ages of onset (within decades) or the presence and type of arrhythmia (for example, atrial fibrillation or sudden cardiac death).

What is the relationship of IDC to heart failure?
IDC is a diagnostic term to describe one of several causes of DCM, and thus as with other cardiomyopathies, heart failure may occur as a consequence. However, heart failure is a clinical syndrome (or symptom complex) that results when cardiac output is not sufficient to meet the metabolic needs of the body. Symptoms commonly include dyspnea on exertion, edema, shortness of breath, and paroxysmal nocturnal dyspnea.

As such, the diagnosis of heart failure requires symptoms to have occurred at some time. In previous decades, the use of the term “heart failure” was usually restricted to the time during acute symptomatic exacerbations, and when acute symptoms resolved the patient was thought to be “out of heart failure.” More common current usage of the “heart failure” term is applied to subjects who have had symptomatic heart failure in the past with ongoing left ventricular dysfunction and intermittent symptoms, even if symptoms are present only with vigorous activities (e.g., early Class II New York Heart Association classification).

 

 

The Genetics of Dilated Cardiomyopathy

Unlike many diseases that have been well described since antiquity, the familial nature of dilated cardiomyopathy has only been recognized in the last three decades, as reviewed by our group in 2005. Scattered case reports prior to 1985 suggested that 1-2% of patients with idiopathic dilated cardiomyopathy (IDC) had family members with a similar condition, termed familial dilated cardiomyopathy (FDC). FDC was therefore thought to be very infrequent, and causes other than genetic were usually suggested to underlie IDC. Systematic studies in the mid-1980s to early 1990s, usually using family history only, suggested FDC rates ranging from 2-10%. The limitation of this approach is that compared to clinical screening, family history alone is quite insensitive to identify affected family members because DCM can be asymptomatic for months or years. Thus, a family member with asymptomatic DCM may be reported as unaffected if cardiovascular clinical screening has not been performed.

When first-degree relatives of individuals with IDC were examined prospectively with echocardiography (echo) and electrocardiography (ECG), FDC rates were observed to range from 10-33%. A key prospective study published in the New England Journal of Medicine in 1992 (The Michels study, 1992) using the most stringent diagnostic criteria (a formal diagnosis of IDC in relatives) demonstrated that FDC was present in 20% of patients with IDC. In that study, only 5% of familial disease was identified by family history alone. When less stringent diagnostic criteria other than a formal diagnosis of IDC in relatives was used (such as isolated left ventricular enlargement, or unexplained heart failure and/or sudden cardiac death in young relatives), two of the largest studies suggested that 35-48% of all patients with IDC have relatives with a similar condition (The McKenna and co-workers report, London, 1998; The Heidelberg report, 1998).

Nomenclature. Since the seminal FDC studies were published, the nomenclature used in genetic DCM research has evolved. It is worth clarifying the various terms referring to the same concept that may be used in the cardiovascular and genetic literature. These are summarized in the table below. After environmental causes (eg., coronary heart disease, valvular or congenital heart disease, toxins or other exposures) are ruled out in DCM cases, the etiology is deemed unknown (Column 1). Pedigree information from these cases is analyzed to classify them as simplex (no family history; column 2, row 1) or multiplex (familial; column 2, row 2). In the clinical cardiovascular literature, when all environmental causes for DCM have been excluded, the term ‘idiopathic dilated cardiomyopathy’ (IDC; column 3, row 1) is used. In some cardiogenetics-oriented literature, the term DCM may also be used to refer to IDC. The term ‘familial dilated cardiomyopathy’ (FDC) is used to denote pedigrees with more than one individual with IDC (column 3, row 2), while all other non-familial cases preserve their IDC categorization (column 3, row 1). Hence, the terms IDC and simplex refer to the same phenotypic observation, while the terms multiplex (or familial) and FDC both refer to familial disease.

DCM Case Etiology

Pedigree Observation

Cardiology Term

Unknown

Simplex – one affected

IDC (may be referred to as DCM in cardiogenetics-oriented literature)

Unknown

Multiplex/familial – multiple affected

FDC

Inheritance. FDC most commonly exhibits familial transmission consistent with autosomal dominant (AD) inheritance (approximately 90%), but X-linked (5-10%), and much less commonly, autosomal recessive (AR) or mitochondrial inheritance have been reported. Preliminary data from our research suggests that DCM-causing mutations may be present in the absence of a family history (apparently sporadic, or simplex, DCM).

Autosomal Dominant FDC. Mutations in greater than 40 genes have been reported to be causative. Most are inherited in autosomal dominant fashion. These genes and the proteins they encode have been provided in the DCM Gene Table.

Clinical Genetic Testing and Genetic Counseling. Clinical genetic testing is available for DCM. The genes included in the currently available testing are those identified in IDC research. Genetic testing for DCM is currently complicated by (1) locus and allelic heterogeneity and (2) the finding that a significant proportion of cases are not attributable to any of the known genes. Larger series of patients will be required to understand gene penetrance, genotype-phenotype correlations, and the true incidence and prevalence of FDC, which will greatly augment genetic counseling.

 

 

Clinical Recommendations

Screening, Diagnosis, Treatment and Counseling

This section provides screening, clinical cardiovascular diagnosis, counseling and treatment recommendations for patients with IDC and families with FDC. We initially published these recommendations in September, 1999 in the Journal of the American College of Cardiology (Crispell K, Wray A, Ni H, Nauman D, Hershberger R. Clinical profiles of four large pedigrees with familial dilated cardiomyopathy: preliminary recommendations for clinical practice. J Am Coll Cardiol 1999;34:837-847, PMID: 10483968). These recommendations were updated in 2005 (Burkett E, Hershberger RE. State of the Art: Clinical and Genetic Issues in Familial Dilated Cardiomyopathy. J Am Coll Cardiol 2005;45:969-81, PMID: 15808750). In March 2009, the Heart Failure Society of America (HFSA) published medical guidelines that reiterate these recommendations (Hershberger, RE et al. Genetic Evaluation of Cardiomyopathy: A Heart Failure Society of America Guideline. J Cardiac Failure, 2009; 15:83-97 PMID: 19254666).

a. The rationale for these recommendations rests on the following points. First and foremost, DCM is a potentially serious, life-threatening disease. Second, screening to detect DCM can be successful, as FDC is much more common than recently thought — the likelihood of FDC in a patient diagnosed with IDC is from 35-50%. Third, effective treatment is available. Extensive clinical trial data supports improved outcomes with medical treatment. Fourth, similar recommendations have been made for other genetic and familial cardiovascular diseases, such as hypertrophic cardiomyopathy, even though medical treatment may not be as effective for hypertrophic cardiomyopathy. Finally, diagnostic, therapeutic, counseling or other interventions assume the voluntary and informed consent of the subject.

b. The diagnosis of IDC most commonly rests on left ventricular enlargement accompanied by systolic dysfunction after ruling out other possible causes of dilated cardiomyopathy. Most commonly, this includes an increased left ventricular end diastolic dimension (LVEDD) at echocardiography adjusted for height or BSA in combination with evidence for systolic dysfunction (ejection fraction <50%). Other causes of dilated cardiomyopathy should be excluded, and includes most importantly ischemic heart disease, which causes ischemic dilated cardiomyopathy. Coronary heart disease should be definitively excluded in patients who appear to have IDC but who are at risk for ischemic heart disease (age > 40 years in men, age > 45 years in women, cigarette smoking, diabetes, hypertension, hypercholesterolemia and other risk factors). Other less common causes of dilated cardiomyopathy can usually be excluded by history, exam, ECG and echocardiography, and include valvular heart disease, rheumatic heart disease, hypertensive heart disease, congenital heart disease, and toxic or drug induced cardiomyopathies such as anthracycline cardiomyopathy.

c. Other non-dilated cardiomyopathies may also be familial, such as hypertrophic cardiomyopathy or arrhythmogenic right ventricular dysplasia. It is usually easy to differentiate IDC/FDC from these other non-dilated cardiomyopathies, but occasionally classification becomes difficult. In these situations comprehensive review of all cardiovascular data from all affected family members can usually lead to the correct diagnostic assignment.

A medical history, an exam, an ECG and an echocardiogram should be performed for first degree relatives (parents, siblings, children) of patients with IDC. Recommending screening for first degree family members is part of the recommendations for the genetic evaluation of DCM. Patients with IDC should be informed about the 35-50% probability of FDC. We then recommend that they inform their first degree relatives of their IDC diagnosis, of the possible familial nature of the disease, and that they should undergo IDC/FDC screening.  Some clinics use educational brochures and template letters that facilitate communication of among probands and at-risk family members.

a. Obtain a targeted family history. Guidelines also recommend obtaining a family history from patients with IDC. The family history includes an assessment for heart failure or “dropsy,” the colloquial term used in previous generations to label heart failure, sudden death not associated with known coronary disease, premature stroke or other history suggestive of heart failure. Other common historical features are sudden death and/or history of heart failure in the peripartum period. Although family history cannot detect asymptomatic DCM, it can be a helpful tool, either in a pictorial or questionnaire format.

The FDC clinical diagnosis is established most simply by diagnosing two (or more) family members with IDC in first or second degree family members. An FDC diagnosis can be established with an IDC diagnosis in more distant relatives (third degree and greater) with greater reliability when three or more family members are diagnosed with IDC. We recommend that the diagnosis of FDC is best made with a bona fide IDC diagnosis in at least two family members. This is in distinction to the assignment of affected status, once the FDC diagnosis has been established in a pedigree, with less stringent criteria (such as isolated left ventricular enlargement  or positive genetic testing results in an unaffected individual). If you are a cardiovascular specialist and would like further review and discussion of this quite technical, but important point, please see our Publications.
Once FDC is diagnosed, pursue stepwise screening. Stepwise screening is progressive screening of first degree relatives of those found to be affected. Thus, first degree relatives of individuals with IDC should be advised to undergo screening (history, exam, ECG, echo) by their physician. If cardiac abnormalities are discovered in any of these relatives (step one of stepwise screening), a full cardiovascular evaluation should follow. For any additional relatives discovered to have IDC, stepwise screening (step 2) should be advised for their first-degree relatives. Thus, it is possible that stepwise screening will identify affected individuals throughout an extended family. A more detailed example of stepwise screening is also given in the For Families section. This clinical recommendation may also identify large kindreds for research. (See Referring Patients for Research Purposes).

In some larger families the most appropriate method to assign affected status in relatives may be to use left ventricular end-diastolic dimension, with or without some measure of fractional shortening (e.g., see Hershberger RE, Ni H, Crispell KA. Familial dilated cardiomyopathy: new echocardiographic diagnostic criteria for classification of family members as affected. J Cardiac Failure 1999;5:203-212, PMID:10496193). Other diagnostic criteria have also been proposed (Mestroni L, Maisch B, McKenna W, et al. Guidelines for the study of familial dilated cardiomyopathies. Eur Heart J 1999;20:93-102. PMID:10099905).

Routine screening beyond first-degree relatives of affected individuals is probably not indicated for clinical purposes, based on our experience. However, affected individuals in some extended families could easily be missed, and thus we suggest the following: (1) comprehensive medical evaluations of any family members with unexplained cardiovascular symptoms, and (2) screening of some second and/or third degree relatives for FDC may be appropriate in some families with particularly troublesome, aggressive or life-threatening disease in the setting of variable age of onset.

We recommend the use of ACE inhibitors and/or beta blockers in family members determined to be affected, following conventional guidelines and community practice standards.
According to the HFSA guidelines, genetic counseling is recommended for all patients with DCM (of unknown cause, IDC) and their family members. Genetic counseling for DCM involves obtaining a family history, identifying at-risk family members, discussing screening options, assessing the most useful genetic test and interpreting results, as well as helping patients to emotionally adjust to having or being at risk for a heart condition.  The educational component of genetic counseling involves informing the patient and family regarding the disease transmission and family risks. Counseling should emphasize that the clinical course of DCM is unpredictable, and ranges from one that is relatively benign with conventional treatment to one of progressive heart failure, and advanced disease resulting in heart transplantation or sudden cardiac death. When FDC is identified, affected family members should also be informed that they have a heritable condition with a genetic risk to their offspring (up to a 50% probability with Mendelian autosomal dominant inheritance). Finally, those who are genetically at risk but have no evidence of LVE should be counseled about the age-dependent penetrance, the possibility of future disease presentation, and clinical recommendations including future surveillance screening or screening at any time with symptoms of cardiac dysfunction.
Ongoing Periodic Surveillance Clinical Screening. According to the HFSA guidelines, surveillance screening (history, exam, ECG, echo) is indicated at the following intervals or at any time that symptoms occur:

Interval if genetic testing is negative and/or if clinical family screening is negative Screening interval if a mutation is present
Every 3-5 years beginning in childhood Yearly in childhood: every 1-3 years

According to the HFSA guidelines, clinical genetic testing should be considered for patients with DCM (of unknown cause, IDC). Any patient with IDC (with or without familial DCM) may benefit from clinical genetic testing. One quarter to one half of patients with IDC will likely have FDC, which is defined as two or more close relatives with IDC. Data from our recent publications, “Lamin A/C Mutation Analysis in a Cohort of 324 Unrelated Patients with Idiopathic or Familial Dilated Cardiomyopathy,” ,”Coding Sequence Mutations Identified in MYH7, TNNT2, SCN5A, CSRP3, LDB3, and TCAP from 313 Patients with Familial or Idiopathic Dilated Cardiomyopathy,” and “Coding Sequence Rare Variants Identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 From 312 Patients With Familial or Idiopathic Dilated Cardiomyopathy” support this recommendation.

The first family member to be tested should be the family member with the clearest diagnosis of IDC. This patient is usually the index patient, but in some families the index patient is deceased and no DNA is available. Considering clinical genetic testing in a patient with a questionable IDC diagnosis or those with little or no evidence of cardiovascular disease may be performed in these scenarios, however, negative results will not be informative. This is because it will be impossible to determine if the person tested negative because he or she does not carry the family gene mutation or because the family gene is not evaluated by the genetic test. The detection rate of currently available genetic tests is approximately 40%. While a positive genetic test result identifying a DCM-causing mutation may aid in a more accurate diagnosis, thus impacting management decisions, surveillance, and therapy, genetic testing is most important in the management of your patient’s family. First degree relatives of an individual with a DCM gene variant each have a 50% chance of carrying the same gene mutation, which significantly increases their chance of developing DCM. At-risk relatives may therefore wish to undergo genetic testing to determine if they have the family variant, as screening and surveillance for DCM are indicated. Because of incomplete, age dependent penetrance and variable expressivity, the symptoms, age of onset, disease features and severity can be very different among members of the same family. Some family members with the gene variant  may have severe disease, while others may have only minor heart muscle and/or rhythm problems. Still others may have no cardiac symptoms or signs of heart problems. “Unaffected” individuals who have a DCM gene variant (those who have the variant but have no evidence of clinical disease as per cardiovascular screening) still have a 50% chance of passing the variant on to each of their offspring, who again could fall anywhere in the clinical spectrum.

A negative test result in the index patient only rules out genetic disease caused by the gene(s) tested. In this case, genetic testing of asymptomatic family members for that gene(s) is not useful. As more genes become available for clinical genetic testing for DCM, the sensitivity of the test increases. Therefore, as the sensitivity of genetic testing panels increases, repeat testing is indicated for people with suspected genetic DCM with prior negative genetic testing results.

 

 

A Review of Genetic DCM Research

This section provides key references for DCM research.

Key Clinical Familial Dilated Cardiomyopathy (FDC) Reports
The Frequency of Familial Dilated Cardiomyopathy in a Series of Patients with Idiopathic Dilated Cardiomyopathy
Michels VV, Moll PP, Miller FA, Tajik AJ, Chu JS, Driscoll DJ, Burnett JC, Rodeheffer RJ, Chesebro JH, Tazelaar HD. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N Engl J Med. 1992; 326:77-82. PMID: 1727235

Familial Dilated Cardiomyopathy: Cardiac abnormalities are common in asymptomatic relatives and may represent early disease.
Baig MK, Goldman JH, Caforio AP, Coonar AS, Keeling PJ, McKenna WJ. Familial dilated cardiomyopathy: cardiac abnormalities are common in asymptomatic relatives and may represent early disease. J Am Coll Cardiol. 1998; 31:195-201. PMID: 9426040

Frequency and Phenotypes of Familial Dilated Cardiomyopathy
Grunig E, Tasman JA, Kucherer H, Franz W, Kubler W, Katus HA. Frequency and phenotypes of familial dilated cardiomyopathy [see comments]. J Am Coll Cardiol. 1998; 31:186-94. PMID 9426039

Familial Dilated Cardiomyopathy: Evidence for Genetic and Phenotypic Heterogeneity
Mestroni L, Rocco C, Gregori D, Sinagra G, Di Lenarda A, Miocic S, Vatta M, Pinamonti B, Muntoni F, Caforio AL, McKenna WJ, Falaschi A, Giacca M, Camerini F. Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. Heart Muscle Disease Study Group. J Am Coll Cardiol. 1999; 34:181-90. PMID: 10400009

Selected DCM Reviews from the Dilated Cardiomyopathy Research Project
Progress in DCM Genetics: The Complexity of a Diverse Genetic Architecture
Hershberger RE, Hedges DJ, Morales AM. Progress in DCM Genetics: The complexity of a diverse genetic architecture. Nature Reviews Cardiology 2013;10:531-47. PMID: 23900355

Where Genome Meets Phenome: Rationale for integrating genetic and protein biomarkers in the diagnosis and management of dilated cardiomyopathy and heart failure
Piran S, Liu P, Morales A, Hershberger RE. Where genome meets phenome: Rationale for integrating genetic and protein biomarkers in the diagnosis and management of dilated cardiomyopathy and heart failure. J Am Coll Cardiol 2012;60:283-89. PMID: 22813604

Clinical and Genetic Issues in Familial Dilated Cardiomyopathy
Hershberger RE, and Siegfried JD.Update 2011: Clinical and Genetic Issues in Familial Dilated Cardiomyopathy. J of Am Coll Cardiol 2011; 57(16): 1641-1649. PMID: 21492761

Clinical and Genetic Issues in Dilated Cardiomyopathy: A Review for Genetics Professionals
Hershberger RE, Morales A, Siegfried JD.  Clinical and genetic issues in dilated cardiomyopathy: A review for genetics professionals. Genetics in Medicine 2010; 12(11): 655-667. PMID: 20864896

State of the Art: Clinical and Genetic Issues in Familial Dilated Cardiomyopathy
Burkett EL, Hershberger RE. State of the Art: Clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll Cardiol 2005; 45:969-81. PMID: 15808750

Guideline Statements for DCM
Genetic Evaluation of Cardiomyopathy – A Heart Failure Society of America Practice Guideline
Hershberger RE, Lindenfeld J, Mestroni L, Seidman CE, Taylor MRG, Towbin JA. Genetic evaluation of cardiomyopathy – A Heart Failure Society of America practice guideline. J Cardiac Failure 2009; 15:83-97. PMID: 19254666

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, riori 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. 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). Heart Rhythm 2011 Aug;8(8):1308-39. PMID: 21787999

DCM Gene Table
Genes Implicated in Cause of DCM

Gene

Protein

OMIM

Estimated fraction of DCM

LMNA

Lamin A/C

150330

0.06

MYH7

β-Myosin heavy chain

160760

0.04

TNNT2

Cardiac troponin T

191045

0.03

RBM20

RNA binding protein 20

613171

0.02

TTN – truncating variants

Titin

188840

0.15 to 0.20

BAG3

BCL-associated athanogene 3

603883

0.03

SCN5A

Sodium channel

600163

0.02

TPM1

α-Tropomyosin

191010

<0.01

PLN

Phospholamban

172405

<0.01

TNNC1

Cardiac troponin C

191040

<0.01

TNNI3

Cardiac troponin I

191044

<0.01

EYA4

Eyes-absent 4

603550

?

MYPN

Myopalladin

608517

0.03

MYBPC3

Myosin-binding protein C

600958

0.02

MYH6

α-Myosin heavy chain

160710

0.04

TMPO

Thymopoietin

188380

<0.01

LAMA4

Laminin, alpha-4

600133

<0.01

VCL

Metavinculin

193065

<0.01

LDB3

Limb Domain-Binding 3

605906

<0.01

TCAP

Titin-cap or Telethonin

604488

<0.01

PSEN1

Presenilin 1

104311

<0.01

PSEN2

Presenilin 2

600759

<0.01

ACTN2

α-actinin-2

102573

<0.01

CRYAB

Alpha B crystalin

123590

<0.01

ABCC9

SUR2A

601439

<0.01

ACTC1

Cardiac actin

102540

<0.01

PDLIM3

PDZ LIM domain protein 3

605889

<0.01

ILK

Integrin-linked kinase

602366

<0.01

SGCD

δ-Sarcoglycan

601411

<0.01

DES

Desmin

125660

<0.01

CSRP3

Muscle LIM protein

600824

<0.01

ANKRD1

Ankyrin repeat domain-containing protein 1

609599

?

NEXN

Nexilin

613121

?

NEBL

Nebulette

605491

?

MURC

Muscle-restricted coiled-coil

No entry

Arrhythmogenic Right Ventricular Cardiomyopathy Genes Implicated in DCM

DSP

Desmoplakin

125647

?

PKP2

Plakophilin 2

602861

?

DSG2

Desmoglein 2

125671

?

X-linked Syndromic Genes in DCM

DMD

Dystrophin

300377

?

TAZ/G4.5

Tafazzin

300394

?

 

 

Genetic Evaluation of Cardiomyopathy

Genetic Evaluation of Cardiomyopathy: A Heart Failure Society of America Practice Guideline is the title of the practice guidelines for the genetic evaluation of cardiomyopathy, including dilated cardiomyopathy, which was published in March 2009 in the Journal of Cardiac Failure Vol. 15 No. 2, 2009. If you would like to obtain a reprint of this publication but are not able to, please contact us and we will assist you.

 

 

Primers

Primers used in Parks SB, Kushner JD, Nauman D, Burgess D, Ludwigsen S, Peterson A, Li D, Jakobs P, Litt M, Porter C, Rahko P, Hershberger RE. Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. Am Heart J 2008;156:161-9.

Protocols and Primers used in Li D, Parks SB, Kushner J, Nauman D, Burgess D, Ludwigsen S, Partain J, Nixon RR, Allen CN, Irwin R, Jakobs, PM, Litt M, Hershberger RE.   Mutations of Presenilin Genes in Dilated Cardiomyopathy and Heart Failure. Am J Human Genetics 2006;79:1030-1039.