Clinical and genetic issues in familial dilated cardiomyopathy

Autosomal dominant (AD)

Familial dilated cardiomyopathy has been reported most commonly (approximately 90%) with AD inheritance (40). The genetic and clinical heterogeneity suggests causation by a single gene, with multiple other genetic and environmental factors altering its expressivity (40). To date mutations in 16 autosomal genes (42–66) have been suggested to be causative of FDC and have been categorized as FDC and FDC with conduction system disease (Table 2).The former category has no specific or unique phenotypic features. The latter category includes families with mutations in lamin A/C who frequently present with sinoatrial and atrioventricular node dysfunction, heart block commonly requiring pacemakers, atrial fibrillation, and other supraventricular arrhythmias; later DCM, ventricular arrhythmias, and death from sudden cardiac death or pump failure are observed. Based on these preliminary reports (Table 2), mutations in the lamin A/C and beta-myosin heavy chain genes may each be responsible for 5% to 10% of FDC. However, these estimates have been derived from patients and their families seen in specialist or referral clinics that may not be representative of overall population frequencies. Actin (67–69) and desmin (69) genes appear to be quite uncommon causes (<1%) of IDC and FDC. Preliminary estimates of the frequencies of the other FDC genes are largely based upon the primary reports (Table 2), but appear to be less common causes of FDC than the lamin A/C and beta-myosin heavy chain genes. Studies designed to survey disease gene frequencies in larger populations will be required to clarify these issues.

X-linked

X-linked FDC is reported to account for approximately 5% to 10% of FDC (Table 2) (38–40), usually resulting from mutations in the dystrophin gene that have been identified in several families displaying X-linked inheritance (70–78). In some cases, DCM has also been noted to be the only or presenting feature in individuals who have Becker muscular dystrophy or in female carriers (79,80). Furthermore, Becker muscular dystrophy and IDC have been seen in the same family (81), suggesting that it may be difficult to draw conclusions about phenotype from genotype. Individuals with X-linked FDC may have skeletal muscle weakness, and whereas most have elevated creatine kinase (CK) levels, normal levels have been reported (40). Dystrophin mutations have also been identified in male patients diagnosed with IDC, suggesting that this may be a rare cause of sporadic cases (20,82).

Mutations in the gene G4.5, which encodes the tafazzin family of proteins, cause Barth syndrome (83) and neonatal non-compaction of the left ventricular myocardium (84). G4.5 mutations have also been implicated as the cause of a nonsyndromic, lethal infantile form of X-linked FDC (85).

Autosomal recessive

A mutation in cardiac troponin I has been shown to cause recessive FDC in one family (86) (Table 2). Autosomal recessive inheritance is more common among certain ethnic groups and may be responsible for some cases of especially young (<10 years) onset (87).

FDC with skeletal muscle disease

Minor skeletal muscle weakness has also been described in a few families with AD FDC (40,88), including two families with lamin mutations (60,61). Affected subjects may have elevated CK levels, but values have been noted to fluctuate from normal to overtly abnormal over time.

Mitochondrial mutations

Mitochondrial point mutations and/or deletions have been reported in individuals with IDC (89–92) and FDC (93,94). However, many of these mutations are found in control subjects as well and may not be the primary cause of the disease, but rather a cofactor in its development (40).

Additional chromosomal loci identified through linkage analysis

Autosomal dominant FDC has been linked to seven additional loci at which no disease genes have been identified. In four of these, cardiac dilatation has been the primary and presenting feature (95–98); in one of these mitral valve prolapse preceded the onset of cardiomyopathy (96) and in another sensorineural hearing loss was associated (97). The remaining three linkage reports describe DCM associated with conduction system disease (88,99,100).

Establishing causality of DCM from gene mutations

One of the most challenging issues in the investigation of genetic causes of DCM is the establishment of causation from a mutation, which in the case of AD inheritance is usually a single base missense or nonsense mutation. How is one convinced that the identified mutation actually causes DCM? The disease phenotype should segregate with the mutation in a large family containing members that have both normal and affected phenotypes. Ideally, these associations can be identified in multiple families. Other evidence that builds the case includes the absence of the mutation in a large control group, the occurrence of the disease gene in a conserved region, finding a de novo mutation, and a plausible pathophysiologic role of the putative disease gene in the development of DCM. Further evidence of DCM in an animal model harboring the same mutation also strengthens the case.

Penetrance and disease expression

Penetrance is a measure of the percentage of individuals who carry a particular gene mutation who are affected by the disorder. For example, for a disorder with 80% penetrance, of those who carry the gene mutation 80% will manifest its effects. This is referred to as incomplete penetrance. Familial dilated cardiomyopathy demonstrates incomplete age-dependent penetrance (for example, see accounts of lamin cardiomyopathy [40,59,62,63]) as well as variable expression. Among individuals carrying a particular gene mutation, there may be wide variability in phenotypic effects and severity, both within and between families. Families therefore often demonstrate a wide range of mild to severe disease across all generations. Within the same family, the disease may range from subtle clinical symptoms and/or mild arrhythmias to sudden death or DCM leading to HF and/or cardiac transplantation. Therefore, it can be difficult to recognize FDC as a single genetic entity when investigating family pedigrees. This variability is crucial to convey in genetic counseling, as an adult with mild or nonpenetrant disease remains at risk for having offspring with a more severe phenotype.

Family history and pedigree analysis

A thorough family history should be taken on every individual with IDC (101–103). Usually targeted family history questions can be used to elicit any obvious family history of DCM or HF. However, recording a three-generation pedigree (including siblings, children, parents, grandparents, aunts and uncles, and nieces and nephews of the index patient) is a more complete, but time-consuming, approach. Pedigree analysis and medical history can provide crucial information but are insensitive when used alone. Nevertheless, until genetic testing is ready for widespread use, clinical screening will remain the most efficient method for early detection of FDC. Furthermore, a distinction should be made between a family history that is negative for cardiovascular disease and one that is inconclusive. In the former case, the patient provides a clear family history, the family is of relatively good size, and no suspicious cardiovascular signs or symptoms or history of known cardiovascular disease are present. In the latter case, the patient may provide a poor or incomplete family history, may have information on few or no family members, and/or the patient or their parents may be adopted. Even though the latter situations reduce the value of family history in a particular case, they do not decrease or exclude the possibility of a heritable cardiovascular disease.

The primary goals of pedigree analysis are to diagnose IDC versus FDC and to identify at-risk family members in order to recommend that they be screened. In the absence of another family member with known IDC, a high level of suspicion should be raised by the occurrence of heart transplantation, HF at an early age (<60 years), or non-specific unexplained sudden death without associated symptoms or history consistent with ischemic heart disease in one or more first or second degree relatives. When the accuracy of medical and family history is in question, medical records and death certificates may be obtained and carefully reviewed to establish accurate histories. The logistics of this is very time consuming, and a referral to a cardiovascular genetics specialist or geneticist may be appropriate in cases where obtaining this documentation is time-prohibitive. Should the clinician undertake this effort, consent for contact is sought via the proband for his or her family members, followed by interaction by the clinician and his/her staff to gain the requisite clinical information.

Despite the importance of family history and pedigree analysis in the care of individuals with IDC and FDC, these elements do not seem to be a routine component of the cardiovascular evaluation for these individuals. Even when a family history is taken in the cardiology clinic setting, complexities of incomplete penetrance and variable expression can easily preclude the diagnosis from those with limited knowledge of clinical genetics. From a survey of 643 Dutch cardiologists (104) regarding their experience with genetic aspects of HCM (a known genetic disease), their self-reported genetic knowledge and skills indicated that 41% did not give genetics information to their HCM patients. Self-reported knowledge about genetics was low, but higher for those who had established a working relationship with a clinical geneticist. It has been proposed that the collaboration of cardiologists and genetics professionals will be most effective to optimize the care of patients with genetic cardiac disease (104,105).

Echocardiographic and electrocardiographic (ECG) screening

Echocardiography and electrocardiography permit safe, sensitive, noninvasive risk assessment. Clinical screening (exam, echocardiogram, ECG) of relatives of patients with IDC and FDC is warranted because a significant proportion of IDC patients have familial disease that may not be detected without formal screening, and once detected may assist in identifying more distant family members who are at risk. Also, FDC gene carriers often do not manifest symptoms of HF or arrhythmias until late in the disease process, usually with moderate or severe LVE and systolic dysfunction. Perhaps most important, early detection by clinical screening may lead to earlier treatment interventions that may slow disease progression.

We have previously recommended that all first-degree relatives (including parents) of patients with IDC undergo echocardiographic and ECG screening regardless of their family history (101,103). The recent American College of Cardiology/American Heart Association HF guidelines have also suggested that screening family members should be considered, and that for a highly positive family history of DCM referral to a cardiovascular genetics center is indicated (102). Despite careful pedigree analysis, it will often not be possible to diagnose FDC without such formal cardiac testing, as relatives with cardiovascular abnormalities (who, if found to be affected, would establish the diagnosis of familial disease) may be asymptomatic. In one study 83% of relatives thought to have preclinical disease on echocardiograms or ECGs were asymptomatic (101). Clinical screening (echocardiogram and ECG) lead to the diagnosis of familial disease in 12% to 15% of apparently isolated (negative family history) IDC cases (32,40), demonstrating its greater sensitivity versus family history alone. When X-linked FDC is suspected, at-risk second-degree relatives should be screened as well.

Diagnosis of FDC

The diagnosis of FDC is made with two or more IDC diagnoses in closely related family members. Echocardiographic diagnosis is most straightforward for individuals with clear LVE accompanied by systolic dysfunction, who thus meet the diagnostic criteria for DCM; these individuals should undergo a full cardiovascular evaluation to rule out detectable causes of DCM such as ischemic etiology before being diagnosed with IDC (or FDC). Additional family members of an FDC kindred who meet diagnostic criteria for IDC can also be given the diagnosis of FDC.

Other diagnostic considerations for affected status in an FDC family

Perhaps the greatest difficulty that arises in screening relatives is determining whether subtle echo and ECG findings are significant and represent early signs of FDC. It has been suggested that LVE may be the single most useful criterion in identifying those with preclinical disease (32,39,106), but other criteria (e.g., the presence of multiple “minor” echocardiographic and/or ECG abnormalities) have also been proposed (19,106). Unlike in some genetic cardiac diseases (e.g., long QT syndrome), no ECG abnormalities are specific to FDC. Common findings include first- or second-degree heart block; atrial, supraventricular, or ventricular arrhythmias; typical or atypical intraventricular conduction delays; or loss of anterior or inferior forces suggestive of infarct patterns. As previously noted, FDC resulting from mutations in lamin A/C (Table 2) should be suspected in families with prominent CSD. Subtle echo findings, especially of ventricular size, are also common, and standardized criteria should be used to assess LV dimensions such as those based on body surface area (107) or the more recent height- and gender-based standards from the Framingham study (108). In some families, reviewing medical records on known affected individuals can provide a partial profile of the initial presentation and natural history of the disease in a particular family. However, because of intrafamilial variability, such retrospective review should only increase suspicion of preclinical disease and not decrease the suspicion of disease in an individual whose phenotype differs from that of known affected subjects.

Serial screening

Because the age of onset varies considerably, normal screening results do not exclude the possibility of future disease (109). Hence, we have suggested that adults with normal screening who have a first-degree relative with FDC should have a repeat echocardiogram and ECG every three to five years (101,109). Those with mild abnormalities or unexplained symptoms may wish to undergo more frequent screening. It may be reasonable to increase the time interval between screening studies for older individuals whose previous studies have been normal.

Considerations in affected but asymptomatic family members

A subset of family members identified to have asymptomatic echocardiographic or ECG abnormalities will progress to have symptomatic disease, including DCM, HF, arrhythmia, and/or sudden death (109). In one study, 27% of relatives found to have asymptomatic LVE by echocardiography progressed to symptomatic DCM over an average three-year follow-up period (39). However, early detection may enable the treatment and prevention of such problems. The use of angiotensin-converting enzyme inhibitors to slow disease progression in patients with asymptomatic IDC and left ventricular systolic dysfunction (as observed in the Studies Of Left Ventricular Dysfunction [SOLVD] prevention trial [110]) may, in a family with FDC, extend to relatives with asymptomatic LVE and normal systolic function. Such therapy has been recommended for some individuals with findings consistent with early disease (101), but outcomes studies to validate this approach in FDC have not yet been undertaken. Similar salutary effects with beta-blockers have been observed when treating subjects with symptomatic HF from either ischemic or idiopathic DCM (102). Both angiotensin-converting enzyme inhibitors and beta-blockers are generally well tolerated; therefore, physicians may wish to maintain a low threshold for their use in family members with evidence of presymptomatic disease, especially significant LVE.

Other recommendations

The potential role of lifestyle modifications for those at risk or with preclinical disease is unknown. Whether the avoidance of activities such as intensive aerobic or strength training may be beneficial is unknown. These issues have been addressed in the HF consensus guidelines (102). Certainly the avoidance of alcohol and illicit drugs should be encouraged; however, the contribution of these environmental factors to the pathogenesis of disease remains to be established. Because of the sudden cardiac death risk it is appropriate for family members to learn cardiopulmonary resuscitation techniques.

Screening children

In screening asymptomatic members of FDC families, clinical disease has been identified in small children and infants. Several of the benefits and limitations of screening adults extend to children, including the possibility for treatment and the unknown significance of some screening results. Guidelines for the age at which children of a parent with IDC or FDC should be screened have not been established. Parents should be alert for symptoms of cardiac disease in at-risk children and should have a low threshold for having them evaluated. More aggressive presymptomatic screening is appropriate with disease onset in childhood in other family members. Echocardiograms and ECGs on children should be evaluated by centers that can interpret pediatric studies.

Limitations of recommendations

No expert panel or consensus guidelines regarding clinical care for patients or families with FDC have been developed. Further, formal prospectively designed studies are needed to substantiate the clinical benefit and cost-effectiveness of these screening and treatment recommendations.

Definition and goals of genetic counseling

Genetic counseling is a communication process that includes both educational and therapeutic elements targeted to patients and their families who face the risk of a genetic disorder (111). The majority of genetic counseling has traditionally been provided by masters' trained genetic counselors or geneticists; however, with greater recognition of genetic disease in all medical specialties, it will be increasingly important for other health providers to provide some level of genetic counseling as well.

A genetic counseling session for patients with or at risk for FDC typically includes 1) a review of the characteristics, genetics, and inheritance pattern(s) of FDC; 2) a thorough family history and pedigree analysis to ascertain the likely pattern of inheritance in the family and identify at-risk relatives; 3) an explanation of the benefits, risks, and limitations of clinical and/or genetic testing for affected individuals and their at-risk relatives; and 4) assisting the family in making psychosocial adjustments to the recognition of a potentially heritable disorder in the family (103,112,113).

Provision of genetic counseling for FDC

There are no established guidelines as to when it is appropriate to refer a patient with IDC/FDC for genetic counseling and, as a result, patients with IDC/FDC seldom receive genetic counseling from any source. As the potential genetic basis for IDC and FDC becomes more widely recognized by the cardiovascular community, cardiologists may provide more information regarding the genetics of IDC/FDC to their patients. Referrals to specialists (e.g., genetic counselors, geneticists, or cardiovascular specialists recognized as experts in genetic cardiomyopathies) may also become more common, especially in cases with severe phenotypes or extended family histories, or upon patient request. In any case, it is imperative for those providing genetic counseling to have the expertise to deal with the genetic and related psychosocial issues within the context of appropriate and up-to-date cardiovascular and genetic diagnosis, management, and insight into prognosis.

Psychosocial issues in counseling

Family members of patients with FDC should be counseled about the potential positive and negative consequences of screening, including clinical and genetic testing, and the associated uncertainties (Table 3).Many report significant anxiety regarding their own risk to develop disease. Undergoing clinical screening and following appropriate interventions may alleviate some anxiety, whether or not screening results are normal. However, that DCM can present with sudden death creates an obstacle to alleviation of anxiety for some.

The current state of genetic testing

Genetic testing for FDC is currently not widely available for two reasons. First, the number of different genes involved in IDC/FDC and the number of different possible mutations in each of these genes (i.e., locus and allelic heterogeneity) makes the development of a comprehensive genetic test difficult. Second, a significant proportion of FDC cases are not attributable to any of the known putative genes, making genetic testing relatively insensitive. It is expected that genetic testing will emerge with the identification of several additional genes that cause or contribute to the FDC phenotype and with advances in deoxyribonucleic acid (DNA) testing technologies. Nevertheless, although sensitive, comprehensive genetic testing may not be widely available for several years, it is prudent to consider the role genetic testing likely will play in the management of individuals with FDC and their families, as well as key issues related to genetic testing. For example, some phenotypes, such as prominent conduction system disease (especially in families requiring pacemakers, see reference 63for summary), raise the suspicion for specific etiologies such as lamin cardiomyopathy, for which testing may soon emerge. The discovery of additional FDC disease genes will augment genetic counseling by enabling prospective studies of gene penetrance, genotype-phenotype correlations, and the true incidence and prevalence of FDC.

Usual indications for genetic testing

Usual indications for genetic testing include confirmation of a known or suspected diagnosis, prediction of the possibility of future illness (presymptomatic testing), detection of the presence of a carrier state in unaffected individuals (whose children may be at risk), and prediction of response to therapy. Because not all IDC is due to inherited susceptibility, other individuals who might consider genetic testing include those with IDC who have a positive family history, family members of individuals with FDC who have an identified mutation, or individuals who have early-onset IDC.

Presymptomatic genetic testing

Presymptomatic genetic testing is testing performed on asymptomatic individuals who are at-risk for a particular genetic condition. The discovery of a gene mutation in such individuals indicates a heightened risk of development of findings related to the condition at some future point. Such testing must begin with an affected family member in order for the testing to be informative. If a putative causative mutation is identified in an affected individual, only then is it possible to offer informative testing to at-risk relatives; otherwise, the purported cause of FDC in the family has not been identified, and a negative test result may not reduce that individual's risk of FDC.

Benefits of genetic testing

Limitations of genetic testing

Genetic testing can provide only limited information about an inherited condition. Such testing cannot determine whether a person will show symptoms of a disorder, the severity of the symptoms, or its natural history. Although some prophylactic treatment measures may improve outcomes for individuals at risk for FDC, they have not been proven, and for some individuals there will be a lack of treatment strategies. Also, testing is limited by the sensitivity to detect genetic causation.

Informed consent process

Many commercial DNA laboratories require written documentation by a specialist before accepting DNA samples for presymptomatic genetic testing.

Clinical versus research genetic testing

Clinical genetic testing is performed by a laboratory subject to regulation by the federal Clinical Laboratories Improvement Act (CLIA), a law passed by Congress in 1988. Most research laboratories are not CLIA-certified and are therefore unable to provide clinical genetic results. Clinical and research genetic testing options are listed in a continuously updated database at the GeneTests/GeneClinics website (114).

Genetic counseling in the absence of genetic testing

For some genetic conditions, the demand for genetic counseling services has been driven by availability of genetic testing. For example, even though genetic counseling for individuals at-risk for breast and ovarian cancer was performed before the widespread availability of BRCA1 and BRCA2 testing, the demand for genetic counseling services increased significantly with the advent of the genetic tests (115). It seems logical that the same pattern would emerge once genetic testing for FDC becomes available.

Facilitating decisions about genetic testing is, however, only one aspect of genetic counseling. Counseling can be beneficial for patients with FDC and their family members for several other reasons. First, early detection and treatment of DCM is beneficial. Dilated cardiomyopathy causes substantial morbidity and mortality and treatment of advanced disease is costly, justifying measures to prevent or ameliorate it in its initial stages through the identification and clinical screening of at-risk individuals. Second, cardiologists often do not recognize FDC in their practices; among those who do, it is likely that few provide accurate risk assessment, genetic education, and screening recommendations. Third, with a diagnosis of FDC a host of difficult psychological, social, and ethical issues unique to genetic disease emerge, which often cannot be addressed in a routine cardiology clinic visit.