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Dilated Cardiomyopathy Overview

, MD and , MS, CGC.

Author Information
, MD
Professor of Medicine, Divisions of Human Genetics and Cardiovascular Medicine
The Ohio State University
Columbus, Ohio
, MS, CGC
Assistant Professor, Division of Human Genetics
The Ohio State University
Columbus, Ohio

Initial Posting: ; Last Update: May 9, 2013.

Summary

Disease characteristics. Nonsyndromic isolated dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and systolic dysfunction, a reduction in the myocardial force of contraction. DCM usually presents with any one of the following:

  • Heart failure with symptoms of congestion (edema, orthopnea, paroxysmal dyspnea) and/or reduced cardiac output (fatigue, dyspnea on exertion)
  • Arrhythmias and/or conduction system disease
  • Thromboembolic disease (from left ventricular mural thrombus) including stroke

Diagnosis/testing. Genetic forms of DCM must be distinguished from other identifiable causes. After exclusion of all identifiable non-genetic causes, DCM is traditionally referred to as idiopathic dilated cardiomyopathy. When two or more closely related family members meet a formal diagnostic standard for idiopathic dilated cardiomyopathy, the diagnosis of familial dilated cardiomyopathy (FDC) is made. The genetic forms of DCM are diagnosed by family history and molecular genetic testing.

Genetic counseling. Genetic DCM can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Maternal mitochondrial inheritance has also been reported; however, mitochondrial forms of DCM, although highly variable in presentation (including mild adult-onset forms), are usually syndromic and thus outside the scope of this review. Genetic counseling and risk assessment depend on determination of the specific DCM subtype in an individual.

Management. Treatment of manifestations: Treatment by physicians skilled in diagnosis and management of symptomatic and asymptomatic DCM improves survival and quality of life. Treatment modalities include pharmacologic therapy, pacemakers, or implantable cardiac defibrillators; cardiac transplantation remains the definitive treatment for progressive DCM and advanced heart failure refractory to medical or device therapy.

Surveillance: Cardiovascular screening (physical examination, echocardiogram, ECG), is recommended: (1) every one to three years when a known disease-causing mutation has been identified in an asymptomatic individual, including children, especially if early onset has been noted in the family; and, (2) every three to five years in adults or children who are first-degree relatives of an individual with idiopathic dilated cardiomyopathy in whom testing has not been performed or a disease-causing mutation has not been identified.

Pregnancy management: Pregnancy is contraindicated in most women with DCM. Pregnant women with idiopathic or familial dilated cardiomyopathy should be followed by a high-risk obstetrician. Asymptomatic women with a family history of idiopathic dilated cardiomyopathy may be at risk for peripartum cardiomyopathy (PPCM) and pregnancy-associated cardiomyopathy (PACM) and warrant management as per guidelines for the evaluation of DCM.

Definition

Clinical Manifestations of Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) may be asymptomatic for a number of years. Presentation usually occurs late in the disease course with any one of the following:

  • Heart failure. Symptoms include those of congestion (edema, orthopnea, paroxysmal dyspnea) and/or reduced cardiac output (fatigue, dyspnea on exertion).
  • Arrhythmias and/or conduction system disease. These commonly accompany advanced cardiomyopathy and heart failure but may also precede heart failure in individuals with an LMNA mutation.
  • Thromboembolic disease. Stroke or systemic embolus, secondary to left ventricular mural thrombus, may also occur.

Onset usually occurs in adults in the fourth to sixth decade, although DCM may present in the fetal period, infancy, early or late childhood, adolescence, and in the elderly. Extensive additional background information is available [Burkett & Hershberger 2005, Sivasankaran et al 2005, Judge 2009, Dellefave & McNally 2010, Hershberger et al 2010a, Hershberger & Siegfried 2011].

Establishing the Diagnosis of Dilated Cardiomyopathy

The diagnosis of DCM is established by the presence of both of the following:

  • Left ventricular enlargement, most commonly assessed by two-dimensional echocardiography, optimally assessed by a height- and gender-based approach [Vasan et al 1997]
  • Systolic dysfunction, a reduction in the myocardial force of contraction
    • An ejection fraction of less than 50% is considered systolic dysfunction. The left ventricular ejection fraction is the most commonly used clinical measure of systolic dysfunction, and is usually estimated from a two-dimensional echocardiogram, from other noninvasive studies (e.g., cardiac nuclear or magnetic resonance imaging studies), or from a left ventricular angiogram.
    • Fractional shortening is another clinical measure of systolic function. A fractional shortening of less than 25% is considered systolic dysfunction.

Establishing the Diagnosis of Idiopathic Dilated Cardiomyopathy

Idiopathic dilated cardiomyopathy is a clinical diagnosis. After exclusion of all identifiable causes (except genetic), DCM is traditionally referred to as idiopathic dilated cardiomyopathy. It is important to note that because the term idiopathic dilated cardiomyopathy was used before evidence of genetic forms emerged, the diagnosis of idiopathic dilated cardiomyopathy does not differentiate between genetic and non-genetic causes; therefore, a portion of individuals with ‘idiopathic dilated cardiomyopathy’ may have genetic forms.

The most common cause of DCM (in which the term DCM is used generically to describe the morphology and function of the left ventricle regardless of etiology) is ischemic injury, such as that caused by coronary artery disease or prior myocardial infarction.

After ischemic injury, other common causes of DCM include valvular and congenital heart disease, toxins (e.g., anthracyclines), thyroid disease, inflammatory conditions, myocarditis, severe long-standing hypertension, and radiation. Most of these can be detected with a careful medical history, a targeted physical examination, results of laboratory testing, an echocardiogram and, if indicated, coronary angiography to exclude coronary heart disease.

Establishing the Diagnosis of Familial Dilated Cardiomyopathy (FDC)

When each of two or more closely related family members meet a formal diagnostic standard for idiopathic dilated cardiomyopathy (i.e., all detectable causes of DCM, except genetic, have been ruled out), the diagnosis of familial dilated cardiomyopathy (FDC) is made [Burkett & Hershberger 2005].

FDC is largely an adult-onset disease, but has demonstrated a highly variable age of onset and reduced penetrance. These issues have been comprehensively reviewed [Burkett & Hershberger 2005, Sivasankaran et al 2005, Judge 2009, Dellefave & McNally 2010, Hershberger et al 2010a, Hershberger & Siegfried 2011].

Peripartum or pregnancy-associated cardiomyopathy (PPCM/PACM). Once considered distinct from DCM, PPCM and PACM (DCM occurring during or soon after pregnancy) are a part of the DCM clinical spectrum. Therefore, clinical and genetic testing recommendations for DCM, as outlined below, apply for PPCM/PACM [Elkayam et al 2005, Morales et al 2010, van Spaendonck-Zwarts et al 2010].

Differential Diagnosis of DCM

Isolated DCM must be distinguished from other cardiomyopathies that may present with left ventricular involvement including arrhythmogenic right ventricular cardiomyopathy (ARVC) with predominant LV involvement [Sen-Chowdhry et al 2008]

DCM must also be distinguished from syndromic forms; a selected list is provided [Hershberger et al 2009a]. Of note, patients with syndromic DCM develop dilated cardiomyopathy and their management should include cardiovascular monitoring (see Management, Surveillance).

  • HFE-associated hereditary hemochromatosis. Hereditary hemochromatosis caused by biallelic HFE mutations is an autosomal recessive disorder associated with cirrhosis, diabetes, hypermelanotic pigmentation, and increased serum iron and ferritin levels. Although iron overload from hemochromatosis can present as DCM, it more commonly presents as non-dilated and/or infiltrative cardiomyopathy.
  • Emery-Dreifuss muscular dystrophy types 2 and 3 is characterized by joint contractures, increased serum creatine kinase (CK) levels, arrhythmias and childhood-onset muscle weakness. Mutation of LMNA has been shown to cause autosomal recessive and autosomal dominant forms.
  • Limb girdle muscular dystrophy 1B, one of the phenotypes included in the LGMD spectrum, is also caused by mutation of LMNA. LGMD1B is autosomal dominant and associated with mild joint contractures, increased CK levels, arrhythmias, and shoulder/hip-girdle weakness.
  • Laing distal myopathy primarily involves facial weakness and childhood-onset weakness of ankles, great toes, finger extensors, and neck flexors. This condition is inherited in autosomal dominant fashion and is caused by heterozygous MYH7 mutations.
  • Carvajal syndrome is an autosomal recessive condition involving DCM with palmoplantar keratoderma and woolly hair. Mutations in DSP are causative.
  • Duchenne and Becker muscular dystrophy are X-linked disorders caused by DMD mutations. In males, features most commonly involve muscle weakness and increased serum CK levels with loss of ambulation in childhood or later in life. Heterozygous (carrier) females may present with isolated DCM.
  • Barth syndrome involves growth retardation, lactic acidosis, neutropenia, and elevated levels of 3-methylglutaconic acid. Hemizygous mutations of TAZ (located on the X chromosome) are causative.
  • Mitochondrial DCM. Maternal mitochondrial DNA mutations have been shown to cause a variety of complex phenotypes, including focal segmental glomerulosclerosis and Kearns-Sayre syndrome, among others.

Prevalence of DCM

The only formal estimate of idiopathic dilated cardiomyopathy prevalence was a study conducted in Olmsted County, Minnesota from 1975 to 1984 that estimated idiopathic dilated cardiomyopathy prevalence (as of 1-1-85) at 36.5:100,000 (~1:2,700) [Codd et al 1989]. This was twice the prevalence of hypertrophic cardiomyopathy (HCM), which was estimated at 19.7:100,000 (~1:5,000) from the same cohort during this study period.

Subsequently, multiple well-designed epidemiologic studies have shown an HCM prevalence of approximately 1:500. It is likely that the Olmsted County study also significantly underestimated the prevalence of IDC, as most experts consider idiopathic DCM to be more common than HCM; however, no further formal population-based epidemiologic studies are available.

Causes

Familial Dilated Cardiomyopathy (FDC)

Isolated (nonsyndromic) DCM of unknown cause (otherwise known as idiopathic dilated cardiomyopathy in the cardiovascular literature) has a genetic basis.

Numerous large kindreds with FDC have provided the foundation for establishing genetic causation, and mutations in more than 30 genes are known to account for approximately 40%-50% of FDC [Hershberger & Siegfried 2011] (Table 1). Simplex cases (i.e., a single occurrence of idiopathic dilated cardiomyopathy in a family) have also been shown to host disease-causing mutations [Hershberger et al 2008, Hershberger et al 2010b].

Approximately 20% of DCM has been attributed to truncating mutations in TTN [Herman et al 2012]. Allelic heterogeneity is the rule; very few mutations have been seen in multiple families.

A few studies have provided evidence supporting a role for copy number variation (CNV) in DCM, including a 4.8-kb deletion in EYA4 [Schonberger et al 2005], a large LMNA deletion found in one proband with familial disease [Gupta et al 2010], and a BAG3 whole-exon deletion in a large family [Norton et al 2011a]. Multiplex ligation probe amplification (MLPA) screening of LMNA in 58 probands failed to identify copy number variants [Norton et al 2011b]. In the absence of large studies, the prevalence of large genomic rearrangements in idiopathic or familial dilated cardiomyopathy remains unknown.

Regardless of whether a DCM-causing mutation has been identified, evaluation of first-degree relatives of a proband with idiopathic dilated cardiomyopathy by echocardiography and electrocardiography (ECG) has shown that approximately 20%-35% of probands will have familial disease [Michels et al 1992, Baig et al 1998, Grunig et al 1998].

Table 1. Molecular Genetics of Familial Dilated Cardiomyopathy (FDC)

Gene SymbolProtein NameOMIM% of FDC Caused by Mutations in This Gene 1Allelic Disorders 2
Autosomal dominant 3
TTN 4Titin18884020%
  • LGMD2J 5
  • Myopathy, early-onset, with fatal cardiomyopathy
  • Myopathy, proximal, with early respiratory muscle involvement
  • Tibial muscular dystrophy, tardive
LMNALamin-A/C1503306%
MYH7Myosin-71607604.2%
  • FHC 6
  • MYH7-related myosin storage myopathy
  • Left ventricular noncompaction
  • MYH7-related scapuloperoneal myopathy
MYH6Myosin-61607103%-4%
  • FHC
SCN5ASodium channel protein type 5 subunit alpha6001632%-4%
MYBPC3Myosin-binding protein C, cardiac-type6009582%-4%
  • FHC
TNNT2Troponin T, cardiac muscle1910452.9%
  • FHC
  • Left ventricular non-compaction
  • TNNT2-related familial restrictive cardiomyopathy
BAG3BAG family molecular chaperone regulator 3 6038832.5%
ANKRD1Ankyrin repeat domain-containing protein 16095992.2%
RBM20Probable RNA-binding protein 206131711.9%
TMPOLamina-associated polypeptide 21883801.1%
LDB3LIM domain-binding protein 36059061%
TCAPTelethonin6044881%
VCLVinculin1930651%
TPM1Tropomyosin alpha-1 chain191010<1%-1.9%
  • FHC
TNNI3Troponin I, cardiac muscle191044?1.3%
  • FHC
  • Restrictive cardiomyopathy
TNNC1Troponin C, slow skeletal and cardiac muscles191040<1%-1.3%
  • FHC
ACTC1Actin, alpha cardiac muscle 1102540<1%
  • FHC
ACTN2Alpha-actinin-2102573<1%
  • FHC
CSRP3Cysteine and glycine-rich protein 3600824<1%
  • FHC
DESDesmin125660<1%
NEXNNexilin613121<1%
  • FHC
PSEN1Presenilin-1104311<1%
PSEN2Presenilin-2600759<1%
SGCDDelta-sarcoglycan601411<1%
  • Delta sarcoglycanopathy (LGMD2F) 5
EYA4Eyes absent homolog 4603550?
PLNCardiac phospholamban172405?
DSG2Desmoglein-2125671
X-linked
DMDDystrophin300377?
TAZTafazzin300394?
  • Endocardial fibroelastosis type 2
  • Familial isolated non-compaction of the left ventricular myocardium

Ordered by mode of inheritance and by frequency in descending order

See Dilated Cardiomyopathy: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

1. The percentages provided (based on ≥2 reports screening large numbers of probands with idiopathic dilated cardiomyopathy or FDC) should be interpreted as preliminary estimates.

2. Allelic disorders = other phenotypes caused by mutation in the same gene

3. Does not include FKTN (encoding fukutin) (see Fukuyama Congenital Muscular Dystrophy) because mutation of FKTN has not been strongly associated with isolated DCM: in one publication mild or no muscular involvement was shown in six individuals from four families. Although only 1/6 apparently had isolated DCM, muscle biopsy was not done in this individual, who was the sib of an individual with muscle involvement [Murakami et al 2006]. Subsequently, Arimura et al [2009] screened 172 persons with DCM and found one compound heterozygote with mild muscle involvement and no brain involvement.

4. Note that the role of mutation of TTN in DCM remains to be fully ascertained because truncating mutations were also identified in 3% of controls, making interpretation of results problematic. Furthermore, some TTN truncating mutations have been observed not to segregate in all families with DCM [Norton et al 2013]. TTN missense mutations may be benign; however, this type of variation has not been formally studied.

5. See Limb-Girdle Muscular Dystrophy Overview.

6. FHC = familial hypertrophic cardiomyopathy

Syndromic DCM

Numerous syndromes, many of which have genetic etiologies beyond those provided in Table 1, have been reported in association with DCM (see Differential Diagnosis). If any of the above features are present, or if family history and/or physical examination suggest extra-cardiac disease, an evaluation by a clinical geneticist is recommended to rule out syndromic disease.

Simplex DCM

The frequency of genetic causation in persons with simplex idiopathic dilated cardiomyopathy (i.e., a single occurrence in a family) has not been formally evaluated and remains largely unknown; however, recent preliminary reports suggest a genetic basis with similar frequency in familial versus apparently simplex disease [Hershberger et al 2008, Hershberger et al 2010b].

Evaluation Strategy to Identify or Confirm FDC

Guidelines for the genetic evaluation of DCM (when idiopathic dilated cardiomyopathy has been established in a proband) have been published [Hershberger et al 2009b].

Recommendations, as outlined below, include a family history, cardiovascular evaluation of first-degree relatives, and molecular genetic testing.

This evaluation strategy aims to identify or confirm FDC and offer appropriate counseling and testing. This approach is particularly relevant because a person with dilated cardiomyopathy (DCM) may remain asymptomatic for years.

Family History

A detailed three- to four-generation family history (including heart failure, DCM, cardiac transplantation, unexplained sudden death, unexplained cardiac conduction system disease and/or arrhythmia, or unexplained stroke or other thromboembolic disease) should be obtained from relatives to assess the possibility of FDC.

A diagnosis of FDC is made when two or more closely related family members have each met a rigorous diagnostic standard for idiopathic dilated cardiomyopathy. With a diagnosis of FDC, family history information is evaluated to determine possible patterns of inheritance.

Both sides of the family should be considered as possibly contributing to familial disease. Families with FDC in both maternal and paternal lineages have been noted, and experience has shown that regardless of an apparent inheritance pattern in a family, assumptions regarding maternal or paternal inheritance of mutations in genes causing FDC in a given family may be unreliable and potentially misleading [Author, personal observation].

Evaluation of First-Degree Relatives of a Proband for Dilated Cardiomyopathy

Current evidence indicates that idiopathic dilated cardiomyopathy may be familial (and therefore possibly genetic) in approximately 20%-35% of cases.

As a part of the evaluation of a proband to identify or confirm FDC, a cardiovascular evaluation of family members to detect any cardiovascular abnormality that would support the diagnosis of dilated cardiomyopathy is recommended. A cascade approach to cardiovascular evaluation should be used, i.e., step-wise evaluation of first degree relatives of persons with idiopathic dilated cardiomyopathy, including medical history, physical examination, echocardiogram, and ECG to determine if any is affected (including asymptomatic disease), thus supporting the diagnosis of FDC [Hershberger et al 2009b].

Because penetrance of DCM is age-dependent, repeat cardiovascular evaluations of at-risk first-degree relatives (to identify or confirm FDC) should be performed at intervals (see Management, Surveillance).

Note: If signs or symptoms of DCM are identified in any individuals evaluated as a part of these family studies, a full cardiovascular evaluation must be sought immediately (see Management).

Molecular Genetic Testing

Genetic testing may be offered to individuals with idiopathic dilated cardiomyopathy, familial dilated cardiomyopathy, peripartum cardiomyopathy (PPCM) or pregnancy associated cardiomyopathy (PACM).

While the literature supports a genetic basis for familial disease, the frequency of genetic causation in simplex cases (i.e., a single occurrence in a family) remains largely unknown. Preliminary data, however, suggest similar mutation frequencies between familial and simplex cases [Hershberger et al 2010b]. Thus, although molecular genetic testing in simplex cases should be considered, firm recommendations for molecular genetic testing in simplex cases cannot be made at this time.

Single gene testing. Few genotype-phenotype correlations are known; however, testing of LMNA, SCN5A, and DES should be considered in those with conduction system disease or with a family history of premature, unexpected sudden death [Hershberger et al 2009b, Ackerman et al 2011].

Multi-gene panel testing. Molecular genetic testing for multiple genes is possible; many genes have been combined into panels of several dozen per platform. Research reports suggest that 40%-50% or more of familial DCM has a genetic basis, suggesting similar detection rates for large multi-gene panels.

A healthcare provider ordering genetic testing using a multi-gene panel should:

  • Carefully review the clinical presentation and family history, as well as the genes included in the panel, as not all panels include the same genes. For example, not all laboratories evaluate mitochondrial genes, which may be more relevant overall for pediatric disease.
  • Be aware that genetic testing panels for DCM are continually updated; thus, repeat testing with a multi-gene panel may be indicated in an individual in whom prior testing with a smaller panel of genes did not identify a disease-causing mutation. This is particularly relevant since mutations in TTN (in which truncating mutations were reported in ~20% of cases) were not evaluated in clinical laboratories until recently.
  • Note that the role of TTN in DCM remains to be fully ascertained because truncating mutations, shown to be most relevant for genetic DCM, were also identified in 3% of controls, making interpretation of results problematic [Herman et al 2012]. Furthermore, reports of lack of segregation of TTN truncating mutations in familial dilated cardiomyopathy illustrated the complexities of TTN variant assessment in the cause of DCM [Norton et al 2013]. TTN missense mutations occur very commonly and most may be benign; however, this type of variation has not been formally studied.

Interpretation of genetic testing results, especially in simplex disease, at this time may be challenging.

  • Because many variants appear to be private, and by definition, in simplex disease other affected family members will not be available for testing to assess segregation, it is likely that some mutations, otherwise meeting usual criteria for a category 2 variant [Richards et al 2008] [ACMG guidelines: “Sequence variation is previously unreported and is of the type which is expected to cause the disorder.”] will be of uncertain significance for DCM pathogenesis (variant of unknown significance [VUS]). Molecular genetic diagnostic laboratory reports vary on the interpretation of these types of variants, in part based on varying degrees of evidence of DCM causation in a specific gene with a category 2 variant. However, it is also possible that a previously identified and validated disease-causing mutation may be identified in an individual with simplex disease.
  • Some probands are also known to harbor more than one rare, at least possibly disease-causing variant, further complicating the interpretation of genetic testing results [Hershberger et al 2008, Hershberger et al 2010b, Li et al 2010].

Any healthcare provider ordering genetic testing must recognize and provide counseling for these outcomes [Burkett & Hershberger 2005, Judge 2009, Caleshu et al 2010, Hershberger et al 2010a, Hershberger & Siegfried 2011]. Given the complexities, a referral to a cardiovascular genetics center should be considered. At such centers, board-certified genetic counselors are especially trained to comprehensively manage these issues, in concert with MD geneticists or cardiologists who are expert in cardiovascular genetic and genomic medicine.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Familial dilated cardiomyopathy (FDC) may be inherited in an autosomal dominant, an autosomal recessive, or an X-linked manner. Most FDC (probably 80%-90%) appears to be autosomal dominant; X-linked and autosomal recessive forms are less common.

Autosomal recessive inheritance, most frequent in consanguineous families and persons with early-onset disease [Hanson & Hershberger 2001], can also result from mutations in genes commonly associated with autosomal dominant DCM.

Although maternal mitochondrial inheritance has also been reported, these forms (which are highly variable in presentation, and include mild adult onset forms) are usually syndromic and thus outside the scope of this review.

Risk to Family Members — Autosomal Dominant Hereditary Dilated Cardiomyopathies

Parents of a proband

  • Some individuals diagnosed as having autosomal dominant DCM have an affected parent.
  • A proband with autosomal dominant dilated cardiomyopathy may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation are included in the evaluation strategy outlined in Evaluation of First-Degree Relatives of a Proband for Dilated Cardiomyopathy. Evaluation of parents may determine that one is affected but has escaped previous diagnosis and/or has a milder phenotypic presentation, including evidence of DCM on echocardiogram without clinical heart failure symptoms (i.e., asymptomatic affected).
  • Parental cardiovascular screening results that do not meet criteria for DCM but do show some abnormality (e.g., left ventricular enlargement but normal function, decreased ejection fraction but normal-sized left ventricle, normal echocardiogram with ECG abnormality) may be early signs of DCM.
  • Because of the variable age of onset, a parent may have normal baseline echocardiogram and ECG results but develop abnormalities at a later time. Thus, normal results on cardiovascular screening do not rule out FDC or the potential risk for DCM, and thus it is suggested that parents with normal cardiovascular testing be rescreened every three to five years.
  • In an unknown proportion of cases, both parents may have evidence of DCM; the proband may, therefore, be at risk of inheriting both or one of these alleles.

Note: (1) Although many individuals diagnosed with autosomal dominant idiopathic dilated cardiomyopathy/FDC have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. (2) If the parent is the individual in whom the mutation first occurred it is possible that s/he may have somatic mosaicism for the mutation and may be mildly affected, although this has not yet been reported.

Sibs of a proband

  • The risk to sibs depends upon the genetic status of the proband's parents.
  • If a parent of the proband is affected and/or shown to have a disease-causing mutation, the risk to the sibs of inheriting the allele is 50%. However, because of variable expression and reduced penetrance, no predictions can be made regarding age of onset or severity of disease.
  • For families in which both parents of a proband have a disease-causing mutation, sibs have a 50% chance of inheriting one of the mutations, and a 25% chance of inheriting both mutations, regardless of the degree of penetrance in the parents.
  • When the parents have no signs of dilated cardiomyopathy, the risk to the sibs of a proband is increased over the general population risk but cannot be precisely calculated. Recommendations for evaluation of sibs are included in the evaluation strategy outlined in Evaluation of First-Degree Relatives of a Proband for Dilated Cardiomyopathy.
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism. When the mutation is known, the sib may be offered genetic testing to help clarify risk. However, the absence of a likely disease-causing mutation in an unaffected sib should be interpreted with caution, as it is possible that some families may have two or more pathogenic mutations.

Offspring of a proband. Each child of an individual with autosomal dominant DCM has a 50% chance of inheriting the parent's mutation. However, because of variable expression and reduced penetrance, no predictions can be made regarding age of onset or severity of disease.

Risk to Family Members — Autosomal Recessive Hereditary Dilated Cardiomyopathies

Parents of a proband

Sibs of a proband

Offspring of a proband. All offspring will obligate carriers if the proband’s reproductive partner does not carry a mutation.

Carrier Detection

If the family-specific mutations have been identified in a DCM-causing gene, carrier testing for at-risk family members may be possible in a laboratory offering either testing for the gene or custom testing.

Risk to Family Members — Nonsyndromic X-Linked DCM Caused by DMD or TAZ Mutations

Parents of a proband

Sibs of a proband

  • The risk to sibs depends on the genetic status of the proband's mother.
  • A female who is heterozygous for a germline mutation (i.e., a carrier) has a 50% chance of transmitting the disease-causing mutation with each pregnancy. Sons who inherit the mutation will be at risk of developing disease; daughters who inherit the mutation are heterozygous for a germline mutation (i.e., carriers) and may or may not be affected.
  • If the mother is not a carrier, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Males with X-linked dilated cardiomyopathy will pass the disease-causing mutation to all of their daughters, who are heterozygotes (i.e., carriers), and to none of their sons.

Other family members of a proband. The proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending upon their gender, may be at risk of being carriers or being affected.

Related Genetic Counseling Issues

See Evaluation of First-Degree Relatives of a Proband for Dilated Cardiomyopathy for information on testing at-risk relatives for the purpose of identifying or confirming the diagnosis of FDC in the family.

See Surveillance for recommendation for ongoing follow up of at-risk individuals for the purpose of early diagnosis of DCM and treatment.

Ambiguous echocardiographic and/or ECG results in asymptomatic at-risk relatives who do not meet criteria for DCM but nevertheless have abnormal cardiac findings (e.g., left ventricular enlargement with normal systolic function, decreased ejection fraction but normal-sized left ventricle, normal echocardiogram but significant conduction system disease and/or arrhythmias), with other causes ruled out, may represent early DCM. Such results complicate family risk assessment and management/surveillance for the individual and other family members.

Molecular genetic testing of at-risk asymptomatic adult relatives of individuals with DCM is possible if molecular genetic testing has identified the specific mutation in an affected relative. Such testing should only be performed in the context of formal genetic counseling, and is not useful in predicting age of disease onset, severity, or rate of progression. Testing of asymptomatic at-risk individuals is predictive testing, not diagnostic testing.

Molecular genetic testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

That said, DCM can occur in infancy and childhood. Furthermore, early diagnosis of DCM may offer a benefit that outweighs the arguments against such testing. Treatment of early DCM may forestall the development of advanced disease and thus justify genetic testing of asymptomatic minors in the setting of early onset and/or aggressive familial disease, where a positive molecular genetic test may guide more stringent clinical screening for asymptomatic but clinically detectable cardiovascular disease.

For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation(s) have been identified in the family, prenatal diagnosis for pregnancies at increased risk may be available through laboratories that offer either testing for the gene of interest or custom testing.

Requests for prenatal testing for (typically) adult-onset diseases are not common. Differences in perspective exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation(s) have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Cardiomyopathy Association (CMA)
    Chiltern Court
    Asheridge Road
    Unit 10
    Chesham Buckinghamshire HP5 2PX
    United Kingdom
    Phone: +44 01494 791224; 0800 018 1024 (UK only)
    Fax: +44 01494 797199
    Email: info@cardiomyopathy.org
  • Children's Cardiomyopathy Foundation (CCF)
    PO Box 547
    Tenafly NJ 07670
    Phone: 866-808-2873 (toll-free)
    Fax: 201-227-7016
    Email: info@childrenscardiomyopathy.org
  • Medline Plus

Management

Treatment of Manifestations

Treatment can favorably (and at times dramatically) affect the natural history of dilated cardiomyopathy (DCM). Management of DCM includes pharmacologic therapy, and pacemaker and implantable cardiac defibrillator device therapy for symptomatic and asymptomatic disease. Care should be provided by physicians skilled in the diagnosis and treatment of patients with heart failure and DCM.

Symptoms include those related to heart failure, arrhythmia, or stroke. Symptomatic DCM represents late disease. Full medical therapy (ACE inhibitors, beta blockers) with evaluation for antiarrhythmic therapy (e.g., pacemakers, implantable cardiac defibrillators) should be considered by cardiovascular specialists with expertise in the field.

Individuals with idiopathic or familial dilated cardiomyopathy should:

  • Be counseled that idiopathic or familial dilated cardiomyopathy is treatable even prior to the onset of symptoms, that treatment may result in remission of DCM, that treatment may forestall symptomatic disease, and that treatment of symptomatic disease (heart failure, arrhythmias, or thromboembolic disease) improves survival and quality of life.
  • Understand the symptoms of heart failure, arrhythmia (including presyncope and syncope), and thromboemoblic disease, and be counseled to urgently seek medical care with the new presentation of any of these symptoms.

Training of relatives and/or caregivers in cardiopulmonary resuscitation (CPR) may be suggested, particularly in families with a strong family history of sudden death and/or significant arrhythmias.

Cardiac transplantation remains the definitive treatment for progressive DCM and heart failure refractory to medical or device therapy.

Additional comprehensive guidelines are available [Hunt et al 2009].

Surveillance

An asymptomatic person with a known disease-causing mutation. Cardiovascular screening (physical examination, echocardiogram, and ECG) should be performed every one to three years.

An asymptomatic at-risk first-degree relative in a kindred with an established diagnosis of FDC in which the family mutation is unknown. Depending on age, cardiovascular screening (physical examination, echocardiogram, and ECG) is indicated every three to five years. If an at-risk first-degree relative has evidence of idiopathic or familial dilated cardiomyopathy, the surveillance recommendations outlined here should extend to that person's first-degree relatives. .

An asymptomatic first-degree relative of an individual with idiopathic dilated cardiomyopathy in whom it is unknown if the idiopathic dilated cardiomyopathy is sporadic or familial should undergo cardiovascular screening (physical examination, echocardiogram, and ECG) every three to five years starting in childhood. If a first-degree at-risk relative shows evidence of dilated cardiomyopathy, a diagnosis of familial dilated cardiomyopathy is made and the surveillance recommendations outlined here should extend to that person's first-degree relatives.

For at-risk relatives with abnormal evaluation results that do not meet criteria for DCM but could be consistent with early DCM (e.g., left ventricular enlargement but normal systolic function, decreased ejection fraction but normal-sized left ventricle, normal echocardiogram with ECG abnormality) [Burkett & Hershberger 2005, Hershberger et al 2010a, Hershberger & Siegfried 2011], full cardiovascular assessment is indicated to evaluate for acquired causes of disease (e.g., coronary artery disease with history of myocardial infarction or history of exposure to cardiotoxic medications) and subsequent yearly screening.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In most cases, pregnancy is contraindicated in DCM.

Pregnant women with idiopathic or familial dilated cardiomyopathy should be followed by a high-risk obstetrician.

Asymptomatic women with a family history of idiopathic dilated cardiomyopathy may be at risk for peripartum cardiomyopathy (PPCM) and pregnancy-associated cardiomyopathy (PACM). Although PPCM and PACM have traditionally been thought to have an etiology separate from familial dilated cardiomyopathy, evidence supporting a genetic basis is emerging [Elkayam et al 2005, Morales 2010, van Spaendonck-Zwarts et al 2010]. Healthcare providers must, therefore, be aware of the possibility of an underlying genetic cause for PPCM/PACM and follow guidelines for the evaluation of DCM (see Evaluation Strategy). Reproductive genetic counseling and genetic testing should be considered in these cases.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

References

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Chapter Notes

Author History

Ray E Hershberger, MD (2007-present)
Jessica D Kushner, MS, CGC; Oregon Health & Science University (2007-2013)
Ana Morales, MS, CGC (2013-present)
Sharie Parks, PhD; Oregon Health & Science University (2007-2013)

Revision History

  • 9 May 2013 (me) Comprehensive update posted live
  • 19 March 2009 (cd) Revision: sequence analysis and prenatal testing available clinically for TCAP, ABCC9, VCL, ACTN2, and CSRP3
  • 10 July 2008 (cd) Revision: clinical testing available for TTN mutations as a cause of dilated cardiomyopathy
  • 27 July 2007 (me) Review posted to live Web site
  • 6 December 2006 (jdk) Original submission
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