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This review focuses on the genetic cardiomyopathies: principally dilated cardiomyopathy (DCM), with salient features of hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), regarding genetic etiology, genetic testing, and genetic counseling. Enormous progress has recently been made in identifying genetic causes for each cardiomyopathy, and key phenotype and genotype information is reviewed. Clinical genetic testing is rapidly emerging with a principal rationale of identifying at-risk asymptomatic or disease-free relatives. Knowledge of a disease-causing mutation can guide clinical surveillance for disease onset, thereby enhancing preventive and treatment interventions. Genetic counseling is also indicated for patients and their family members regarding the symptoms of their cardiomyopathy, its inheritance pattern, family screening recommendations, and genetic testing options and possible results.
Enormous progress has recently been made in identifying the genetic causes of cardiomyopathy, which, in turn, has enabled greater understanding of molecular mechanisms underlying each disease. This progress has also increased the probability of establishing specific genetic diagnoses, thereby providing new opportunities for practitioners, patients, and families to utilize this genetic information.
When considering whether a patient may have a cardiomyopathy, the approach is guided foremost by the patient's phenotype (clinical features). These clinical features include cardiovascular data, such as those derived from echocardiographic studies (ventricular size, function, wall thickness, and wall motion), and electrocardiographic (ECG) findings. More elegant studies, such as magnetic resonance imaging (MRI), may also complement a cardiomyopathy evaluation. A detailed medical history (including age of onset, type of symptoms), a physical examination (to rule out syndromic disease), and a 3-4 generation family history are also important. This cumulative phenotypic information drives assignment of a specific cardiomyopathy diagnosis.
While most genetic cardiomyopathies only involve the heart, establishing a phenotypically-driven cardiomyopathy diagnosis at times requires recognition of key features of syndromic forms. A syndrome is a recurring pattern of defects that most likely represents a single etiology. In most cases of cardiovascular syndromic disease, multiple tissues and/or organ systems are involved. Thus, the cardiovascular practitioner must be alert for signs and symptoms beyond the cardiovascular system. For example, Noonan syndrome, which can be associated with four genes (none associated with isolated HCM), presents with cardiac hypertrophy, short stature, variable degrees of developmental delay, and dysmorphic features (see link within1 for references, and Table 1).
In addition to phenotypic data, a great deal of information regarding the genotype - the genetic makeup - of individuals with cardiomyopathy is now available that can provide a genetic cause to a newly rendered, carefully phenotyped clinical diagnosis. Different mutations in the same gene (allelic heterogeneity) may give rise to virtually identical phenotypes; however, this can also lead to strikingly different phenotypes. This is exemplified by LMNA mutations, which lead to multiple allelic phenotypes, collectively referred to as laminopathies (see links within2 for references). LMNA allelic disorders include isolated DCM, syndromes that may involve DCM (eg: Emery-Dreifuss muscular dystrophy) or disorders not associated with DCM (eg: lipodystrophy and Hutchinson-Gilford progeria; Tables 1, ,22).
With a causal genetic mutation identified in a proband, closely related at-risk family members can choose to undergo genetic testing to determine whether they carry the same mutation. Such information may be extremely helpful in guiding clinical screening for evidence of disease in presymptomatic individuals, counseling patients regarding disease presentation, and facilitating life-saving interventions.
Guidelines for the care of patients with suspected or known genetic cardiomyopathy are only now emerging, usually organized by phenotype rather than by genotype. However, as much larger studies linking clinical and genotype data are conducted, genotype-based diagnoses will become more routinely used to characterize cardiomyopathies.
Discoveries of mutations in genes that cause DCM were made possible from early studies in families with idiopathic dilated cardiomyopathy (IDC). In the early 1980's only 1-2% of IDC cases were thought to be familial, as previously reviewed in detail.4 Studies in the later 1980's showed that 5-10% of IDC cases were familial, whereas in the 1990's, with more rigorous study designs and larger cohorts, the familial rate was shown to range from 20-50% when comprehensive clinical screening (history, exam, ECG and echocardiogram) was undertaken (see4 for extensive review).
Familial dilated cardiomyopathy (FDC) has been defined as two or more closely related family members meeting diagnostic criteria for IDC.4, 5 Genetic etiology was suspected in these families because of the multigenerational nature of the disease and transmission usually indicating an autosomal dominant pattern of inheritance.
Previous comprehensive reviews have summarized the clinical features and presentation of IDC.6 Most studies have failed to identify significant features that differ between patients with IDC and those with FDC, including age, gender, or clinical signs or symptoms at presentation.7, 8
A three- to four-generation family history has been recommended with a new diagnosis of IDC, despite recognition that family history alone is insensitive compared to full clinical screening (history, exam, ECG, echocardiogram).4, 9
Clinical onset of FDC is usually in the adult years (30's to 50's), but varies widely, occasionally even presenting in infants, small children, and the elderly. Like IDC,6 FDC most commonly presents with advanced disease, including heart failure, arrhythmia, stroke or embolus, the latter from mural thrombus.4 Family studies have demonstrated that clinically silent FDC can be present for years, but large natural history studies of asymptomatic individuals with either IDC or FDC are not available.6
More than 20 genes have been identified as causes of DCM, representing marked locus heterogeneity (Tables 1, ,2).2). For most of these genes, allelic heterogeneity is the rule. The genes implicated in DCM code for a variety of proteins expressed within the cardiomyocyte, ranging from the nuclear envelope, the cardiac sarcomere, ion channels, transcription factors, and the dystrophin-associated cytoskeletal complex (Table 2). Numerous excellent reviews are available that provide additional detail.4, 10-17 Mitochondrial defects have also been identified4, 13, 17 (Tables 1, ,22).
One of the genes associated with DCM, the LMNA gene, which encodes the type-A lamins, A and C, has been reported to be causative of DCM in 4-8% of patients with IDC/FDC (Table 2). The lamins are critical structural elements of the inner nuclear membrane. LMNA mutations were observed in 5.9% of probands in a cohort of 324 unrelated patients with IDC/FDC, the largest series to derive a frequency estimate to date.18 Other common genetic causes of DCM include mutations in beta-myosin heavy chain (MYH7) and cardiac troponin T (TNNT2) (Table 2). Numerous other genes have been associated with FDC, most of which are autosomal, although two X-linked genes are also included. The mutation frequencies provided in most cases should be considered preliminary, as usually only one or two primary reports focusing on single genes are available from which to estimate frequencies. One larger cohort8 has been sequenced for seven genes.18, 19
Penetrance of disease in families with FDC is highly variable, and, common to most adult-onset genetic disease, age-dependent. Penetrance estimates have been suggested to be 10% at < 20 years; 34% between 20-30 years; 60% between 30-40 years, and 90% at 40 years, although genetic screening was not accomplished in this report.20
HCM is a genetic cardiomyopathy structurally characterized by left ventricular hypertrophy (LVH), predominantly of the interventricular septum, myocyte disarray and fibrosis. It affects approximately 1/500 (0.2%) individuals. Although the HCM designation is commonly restricted to hypertrophy arising from mutations in genes encoding sarcomeric contractile proteins, other non-syndromic, genetic causes of the hypertrophic phenotype are additionally captured by this nomenclature (Tables 1, ,33).
Unlike DCM, which is primarily an adult-onset disease, HCM arising from mutations of genes encoding sarcomeric proteins most commonly occurs at puberty. Diastolic dysfunction typically precedes overt hypertrophy or symptoms of heart failure. Approximately 20% of individuals will develop atrial fibrillation, which can be associated with embolic stroke. Approximately 25% of individuals with HCM survive to age 75 or older with low (1%) overall annual mortality rates. Left ventricular outflow tract obstruction confers a higher risk for morbidity and mortality. Sudden cardiac death, primarily resulting from ventricular arrhythmias, is also a common cause of mortality and often serves as the presenting manifestation of disease.
Cardiac hypertrophy is a major phenotypic component of a number of syndromes, including various mitochondrial disorders (Tables 1, ,3).3). Some syndromic forms, such as Fabry and Danon diseases, display X-linked patterns of inheritance, which can aid in distinguishing them from HCM, particularly in cases where syndromic features are absent.21, 22
Clinical management for HCM involves not only amelioration of symptoms, but also prevention of SCD and screening of at-risk family members. These topics are covered in reviews23, 24 and consensus guidelines.25
HCM usually follows an autosomal dominant pattern of inheritance, characterized by substantial variation in expressivity and age-dependent penetrance. It is caused primarily by missense mutations in genes encoding components of the cardiac sarcomere, although causative nonsense, frameshift, and in-frame insertion/deletion mutations have also been observed, particularly in MYBPC3, which encodes cardiac myosin-binding protein C26 (Table 3).
Unlike DCM, mutations in two genes, MYH7 and MYBPC3, account for approximately 80% of HCM cases when genetic cause is found,1, 26, 27 but similar to DCM, marked allelic heterogeneity of these genes is the rule with most mutations occurring privately or at frequencies less than 1%. Mutations in three other genes, TNNT2, TNNI3, and TPM1, encoding components of the troponin complex, are also relatively common (collectively approximately 10-15% when genetic cause is found).1, 26-28 Mutations have been identified rarely in additional sarcomeric genes29 (Table 3). Currently nine genes are available for clinical genetic testing,1 and of all patients who undergo genetic testing, a mutation is identified in 40-60% of sporadic and familial cases when testing is performed for these genes.26, 27
Some patients (2-5%) harbor two mutations in causative sarcomeric genes.26, 30, 31 Because these patients exhibit more severe and earlier onset hypertrophy,30 it has been proposed that one mutation may act as a modifier to the other.26
ARVD/C is an uncommon disease characterized by right ventricular (RV) fibro-fatty replacement, RV myocyte loss and RV wall thinning.35 Standard diagnostic criteria have been established35 and revised,36 and include functional and structural alterations of the RV (principally fibrofatty replacement of the free wall), ECG depolarization/repolarization changes, arrhythmias/conduction abnormalities, and family history. Onset usually occurs during adolescence or young adulthood, although presentation during the fifth decade has been observed. Sudden cardiac death and/or exercise-induced ventricular arrhythmia are often presenting features. Death usually occurs as a result of ventricular tachycardia or, less commonly, heart failure. Despite being primarily a disease of the RV, LV involvement may also be present and can precede RV manifestations37 or even be the presenting feature.38 Management guidelines have been established as a component of more general arrhythmia guidelines. Family history intake is recommended;9, 35, 39 however, given low penetrance and clinical variability, as well as the possibility of non-syndromic autosomal recessive ARVD/C, absence of familial disease does not rule out genetic risk. Because of this, clinical screening of first-degree relatives is recommended at intervals.
One-third to one-half of ARVD/C cases are familial. The pattern of inheritance is autosomal dominant with variable expressivity and reduced penetrance (20-30% or higher, particularly in males). Eight causative genes have been identified, most of which encode cardiac desmosomal proteins (Table 4).
Pathologically, ARVD/C may be mediated by desmosomal defects predisposing to myocyte damage,39, 41 followed by inflammation and fibro-fatty replacement.39 Other arrhythmogenic mechanisms may involve gap junction remodeling42 and Wnt signaling defects.43 A genetic cause remains unknown in approximately 50% of cases (Table 4).
Guidelines for HCM,25, 44, 45 DCM45, 46 and ARVD/C45 are available, as is expert opinion and currently available genetic testing at the Genetests website (www.genetests.org) for HCM,1 DCM3 and ARVD/C.40 Generic guidelines for all practitioners who diagnose and manage these cardiomyopathies can be summarized as: 1) obtain a careful family history of at least three to four generations; 2) recommend clinical screening in at-risk-relatives (e.g., echocardiogram, ECG, history, exam, etc., and other specialized testing as appropriate for the cardiomyopathy); 3) counsel the patient that the condition may have a heritable genetic basis, and discuss its likely pattern of inheritance, the typical age of onset, presenting symptoms, and other relevant features; and 4) consider and conduct genetic testing, as appropriate.
In some patients these recommendations are straightforward, while in others, gaining family history data, providing counseling, or undertaking decisions regarding genetic testing are more complex and problematic. Especially in the latter cases, referrals to geneticists or cardiologists specializing in cardiovascular genetic medicine47 may be desirable and should be considered.
Genetic counseling is a helpful adjunct to assist with the diagnosis and management of the cardiomyopathies.48-50 It is also an essential component of any genetic testing process.50 In North America, genetic counseling is traditionally carried out by board certified, masters-trained counselors (an increasing number specializing in cardiovascular genetic medicine)47 in collaboration with physicians.
The genetic counseling process has four principal components, including: 1) acquiring a complete family history; 2) providing information regarding the modes of inheritance and clinical features of the cardiomyopathy; 3) presenting the benefits, risks, limitations, and possible outcomes if genetic testing will be offered, and 4) discussing with the patient and family the potential psychosocial impact of a heritable disease. Recent reviews provide comprehensive information regarding these topics, including genetics glossaries for those less familiar with genetic terminology.9, 50
A thorough family history of cardiomyopathy and any other cardiovascular or genetic disease is obtained as a three- to four-generation pedigree. Pedigree analysis follows, which allows clinicians to observe familial patterns, discover possible genetic risk factors, and identify at-risk family members for whom clinical screening and genetic testing may be indicated.
The rationale for genetic testing in cardiomyopathy at this time is principally to identify a disease-causing mutation in those at-risk family members who have little or no evidence of disease so that heightened clinical surveillance, more informed medical management, and/or reproductive decision-making can be undertaken.45, 47 Increased clinical surveillance, in turn, can lead to early intervention, thereby preventing sequelae of advanced disease. The bedrock underlying this rationale is that treatment interventions are available that can prevent, delay or treat almost all of the morbid or mortal aspects of the cardiomyopathies.45, 47 In this respect, cardiovascular genetic disease varies from many other genetic diagnoses that have no known interventions to affect their natural history.47
Genetic testing may be useful for the sole purpose of clarification or confirmation of disease etiology in an affected individual with cardiomyopathy; knowledge of causation in a disease considered to be idiopathic, for example IDC, may have considerable intrinsic value. Genetic testing may also be useful for diagnosis or clinical management, such as distinguishing between adapative hypertrophy to exercise (athlete's heart) and HCM, or assessing risk for progressive conduction system disease and/or arhythmia in a person with DCM.
Genetic testing, although rapidly emerging into clinical practice, is currently undertaken at only a few centers.47 Further, because of the relative insensitivity of genetic testing for DCM, and intermediate sensitivity for HCM and ARVD/C, testing is usually limited to the most common causative genes.50 This approach may be rapidly changing as more cost-effective screening methods, such as chip-based or next generation sequencing, become available. Also, with the recent passage of the Genetics Information Nondiscrimination Act (GINA), interest in and utilization of genetic testing services is likely to increase. Time and cost, however, remain pertinent considerations.51 Additionally, insurance coverage is variable, further confounding access to testing. Research genetic testing, the mainstay for most of the past 15 years, may be an option if clinical genetic testing is unavailable or is otherwise uninformative; however, this testing typically takes months to years to complete, and often requires mutation confirmation through a CLIA-certified lab.50 Nevertheless, research testing of large cohorts of patients and family members is essential to continued progress in the field, and referrals of patients with genetic cardiomyopathies for clinical research and longitudinal follow up have been advocated.45 Clinical and research testing availability are catalogued by GeneTests (www.genetests.org), a continually updated medical genetics resource.
To increase the likelihood of finding a causative mutation, genetic testing should begin with the family member manifesting the most obvious disease.50 If the proband's results are negative, further testing in the family is often of little utility, particularly testing of asymptomatic relatives. For autosomal dominant disease, a positive result implies that the proband's offspring will be at 50% risk of inheriting the gene mutation and testing should be made available to them.
Although causative mutations for DCM have been identified in more than 20 genes, preliminary data suggests that mutations in these genes account for a minority of cases, probably at best 20-25% (Table 2). Depending on the phenotype and family history, testing may begin with LMNA, MYH7, and TNNT2 because of their higher frequencies (Table 2). Negative results for these three genes may then warrant reflex testing to the remaining genes.
Of particular note, onset of conduction system disease with minimal cardiac dilatation is suggestive of LMNA-related DCM. It has also been suggested that all individuals with IDC should undergo genetic testing for mutations in LMNA,2, 18, 45, 50 given relatively higher mutation frequencies in this gene.
Clinical testing is available for nine sarcomeric genes associated with HCM, with genetic causation identifiable in approximately 40-60% of families.26, 27 Genetic workup may begin with MYH7, MYBPC3, and TNNT2, as mutations in these genes account for the vast majority of cases (Table 3). As with DCM, definitive genotype-phenotype correlations remain elusive, in part because of extreme genetic heterogeneity, rarity of individual mutations, and substantial variation in penetrance and expressivity, even among related individuals carrying identical mutations. TNNT2 testing may be considered first if a family presents with SCD or mild hypertrophy. If no mutation is found in these three genes, testing can reflex to the remaining clinically available sarcomeric genes. Since any LV wall thickness can be associated with an HCM mutation, genetic testing is feasible for any level of hypertrophy.25
Genetic testing can be useful in the setting of ARVD/C, where SCD is a common presenting feature. Results compiled from multiple cohorts tested for DSP, PKP2, DSG2, DSC2, and TGFB3 suggest that the detection rate is 40-50%.41 Since PKP2 mutations are identified in relatively higher proportions43 (Table 4), it is reasonable to begin testing with PKP2 and, if negative, consider reflex testing. A few genotype/phenotype correlations have been suggested: RYR2 has been associated with early-onset cardiac death and effort-induced polymorphic ventricular tachycardia, TMEM43 with fully penetrant disease, and DSP or DSG2 with LV involvement.
Genetic testing should be considered in the context of strong clinical data. Furthermore, although DCM, HCM, and ARVD/C tend to follow an autosomal dominant inheritance pattern, multigenic and homozygous forms have been reported.26, 28, 30, 31, 37 Thus, the complexity of testing options and inheritance patterns in hereditary cardiomyopathies warrants involvement of cardiovascular genetics experts and ongoing collaboration between cardiologists and genetic professionals.
Enormous progress has been made in identifying and understanding the genetic basis of cardiomyopathy. The field is rapidly evolving and the future appears bright. Ongoing research efforts now aim to identify additional genetic cause, particularly for DCM. Newer, faster sequencing methods are being developed that will help us achieve more rapid and cost effective molecular genetic diagnoses. Also critical for progress will be the conduct of long term natural history studies with large cohorts of patients and their family members known to carry disease-causing mutations. This future is underway: although still incomplete, genetic cardiomyopathy knowledge has already led to relevant, achievable clinical recommendations for the screening of at-risk family members, for genetic counseling, and for genetic testing.
Funding Sources: This work was supported in part by NIH award RO1-HL58626 (Dr. Hershberger).
Conflicts of interest: none.