TTN encodes the largest protein expressed in the heart and is the gene most frequently associated with DCM. The titin protein spans from the Z-disc to the M line in the center of the sarcomere and is responsible for maintaining sarcomere structural integrity. Many TTN mutations are truncating (frameshift mutations, nonsense mutations, and mutations generating RNA splice variants), and many of these truncating TTN mutations show an autosomal dominant association with DCM that explains 14% to 25% of cases of this disease.7,8 Most of the identified disease-causing mutations are located in the titin A-band and affect TTN exons included in many of the different titin isoforms.9 Other phentoypes linked to titin truncations are tibial muscular dystrophy and some recessive diseases, such as type-2 limb-girdle muscular dystrophy and early onset skeletal and cardiac myopathy. An early study of TTN truncations in DCM found no relationship between the presence of TTN mutations and the rate of cardiac outcomes; however, analysis by sex revealed that male mutation carriers had adverse events at a younger age.7 A more recent analysis demonstrated a higher prevalence of ventricular arrhythmia in carriers than in noncarriers (64% vs 21%), albeit in a small study population.10 Larger studies have reported a 3-fold higher risk of atrial fibrillation or ventricular tachycardia after adjusting for conventional risk factors. In one study, arrhythmias were detected in 46% of DCM patients with TTN truncations vs 33% of DCM patients not carrying these mutations.11 Another study reported a more positive prognosis for DCM patients with TTN truncations than for their counterparts with mutations in LMNA or with no identified genetic cause; patients with TTN truncations had less severe disease at presentation and responded more favorably to standard therapy.12 Our recent study presented at the 2018 European Society of Cardiology Congress analyzed data from more than 500 index patients and family members with TTN mutations. The study revealed an elevated rate of cardiovascular death in affected individuals older than 30 years; the mortality rate was higher for men than for women, and sudden cardiac death accounted for half of the events.13

Genes encoding sarcomere proteins are strongly associated with the development of hypertrophic cardiomyopathy (HCM) through autosomal dominant inheritance.14 However, most of these genes are also implicated in DCM. The most frequently affected genes are MYH7, TNNT2, and TPM1, whereas MYBPC3 gene variants are less common. The presence of these mutations has been linked to the early development of DCM, characterized by early onset heart failure in the absence of previous evidence of hypertrophy or myofibrillar disorganization, thus indicating primary DCM.15 Another study of rare sarcomere gene variants in DCM showed an increase in the rate of events (death and heart transplantation) after the age of 50 years, independently of the ejection fraction; however, carriers and noncarriers showed no difference in overall long-term survival.16 The prognostic impact of MYH7 genetic variants depends on the location of the mutation in the expressed protein. Missense variants in the converter region (amino acids 709-777) have been linked to early disease onset and a high prevalence of events.17 Even within this region, different mutations have markedly distinct effects on disease progression and prognosis. In particular, mutations in the alpha helix spanning amino acids 715 to 722 are associated with an especially poor prognosis, including a high rate of sudden cardiac death among young patients and heart failure leading to death or heart transplant before the age of 50 years (Figure 1). Another functionally important region appears to be the actin-binding domain (amino acids 526-557), with genetic variants identified in 64 carriers from 30 families; most patients with these variants were diagnosed early in life and developed moderate ventricular dysfunction (unpublished data). It is not possible to describe a general prognosis for mutations in TTNT2; however, those that cause DCM tend to be highly penetrant and are associated with a high frequency of adverse events.18 Several missense mutations linked to DCM have been identified in TPM1, clustering in the central flexible region in the C-terminal domain (amino acids 81-258). Many of these mutations have been linked to disease in early childhood, sometimes with events principally triggered by heart failure.19 It should be noted that mutations in MYBPC3 are not generally associated with poor prognosis; however, they can give rise to severe phenotypes in homozygotes or compound heterozygotes.

Figure 1.

Kaplan-Meier curves estimating cardiovascular-death–free survival in carriers of disease-causing missense mutations in MYH7. (Cardiovascular death includes sudden cardiac death, death related to appropriate defibrillator discharge, death due to heart failure or heart transplantation, or death due to any other cardiovascular cause.) Events in carriers of any disease-causing missense mutations (gray) are compared with events associated with the converter region (amino acids 709-711; green), the alpha helix spanning amino acids 715-721 (violet), and the p.Gly716Arg missense variant (brown). The chart reveals significant differences for mutations in different regions, with alpha helix variants such as p.Gly716Arg associated with very poor survival at the age of 50 years. An initial or later diagnosis of dilated cardiomyopathy was more frequent in patients carrying variants linked to a poor prognosis than in those carrying variants linked to a better prognosis.

(0.17MB).

Actin, encoded by the ACTC1 gene, is the principal component of the thin filaments in the sarcomere. Of the few mutations reported for this gene, some are linked to an overlapping phenotype of noncompaction HCM and autosomal dominant DCM. Some of the described ACTC1 genetic variants are associated with septal defects, and progression to heart failure in these patients is characterized by diastolic dysfunction and a restrictive cardiomyopathy phenotype.20

The LMNA gene encodes 2 proteins, lamins A and C, which are components of the inner nuclear membrane. Mutations in this gene are associated with a group of autosomal dominant inherited diseases known collectively as laminopathies. Laminopathies involving lamin A/C include DCM, Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb-girdle muscular dystrophy, Charcot–Marie–Tooth disease, and progeria. Cardiac involvement is characterized by a high risk of sudden cardiac death and high rates of conduction disorders and ventricular arrhythmias, which generally precede the onset of ventricular dysfunction.21LMNA genetic variants are also frequently associated with supraventricular arrhythmias (atrial fibrillation). Penetrance is very high, with almost 100% of mutation carriers developing the disease by the age of 60 years. A low threshold is recommended for placing an implantable cardioverter-defibrillator (ICD) in these patients, especially those requiring pacing.22,23 The most frequently described genetic variants are missense mutations located in the central domain of the protein; however, there have also been reports of truncation variants. Carriers of the disease-causing mutations have a poor prognosis, but the mutations differ in their effects, and some rare variants do not cause disease. A European cohort study identified 4 factors that independently increase the risk of arrhythmias in mutation carriers: the presence of nonsustained ventricular tachycardia, an ejection fraction <45%, male sex, and nonmissense mutations (nonsense, frameshift, and splicing mutations).22 Nevertheless, in an analysis of data from more than 1000 LMNA mutation carriers and their family members, our group found no major differences in adverse events between men and women (unpublished data). Moreover, preliminary results from a Spanish multicenter study showed no prognostic differences between truncating and missense mutations in LMNA.24 These data indicate the need to revise the criteria currently used to indicate ICD placement in these patients, especially given that sudden cardiac death is not infrequent in patients with an ejection fraction> 45%.25

The cytoplasmic protein desmin is the major component of intermediate filaments and is encoded by the DES gene. Mutations in DES have been linked to DCM, conduction disorders, and progressive muscle weakness and are highly penetrant. Autosomal recessive and autosomal dominant mutations have been identified, and most of the disease-causing variants arise from missense mutations. The prevalence of desminopathies is approximately 1 in 10 000.26 In the heart, conduction disorders tend to precede myocardial alterations, and the cardiomyopathy is frequently restrictive.27 Up to 50% of carriers develop cardiomyopathy, and approximately 60% have conduction disorders and ventricular arrhythmias. The absence of cardiomyopathy does not equate to absence of disease. Although atrioventricular block is a characteristic feature of desminopathy, fatal arrhythmia has been reported, including in patients fitted with a pacemaker.28

Dystrophin is a large cytoskeletal protein located on the inner surface of the sarcolemma and is encoded by the DMD gene. Mutations in DMD are associated with 3 phenotypes: Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked DCM. These phenotypes differ in the severity of muscle involvement. DMD-associated DCM can affect male and female carriers of disease-causing mutations, with diagnosis between the ages of 20 and 40 years for men and a little later for women. Progression to severe disease tends to be rapid in men, whereas it can take several years in women. Cardiac deterioration is detected in 60% to 75% of patients and is characterized by diffuse ventricular degeneration and fibrosis, especially in the inferolateral regions and conduction tissue. The disease frequently features atrial and ventricular arrhythmias. In more than 2 out of every 3 patients, the mutation involves the deletion of 1 or more exons, most often in a specific region between exons 45 and 53. A small proportion of affected individuals (5%-15%) have partial DMD gene duplications. Missense mutations are less frequent and generally affect heart-specific regions of the protein; more than half of the DCM-related missense mutations in DMD are located in the actin-binding domain.29,30

The X chromosome EMD gene encodes the nuclear membrane protein emerin, a serine-rich member of the family of lamin-associated nuclear proteins. Mutations in EMD are associated with X-linked Emery-Dreifuss muscular dystrophy, which is characterized by early onset joint contractures appearing in childhood or adolescence; progressive limb weakness and atrophy; and cardiac involvement featuring conduction disorders, ventricular arrhythmias, and DCM. Sudden cardiac death in affected patients can be triggered by asystole and is therefore preventable by pacemaker implantation; however, in some patients there is a risk of sudden death from fibrosis related to the cardiomyopathy, thus requiring placement of an ICD.31,32 Female mutation carriers tend to have a less severe phenotype or do not develop the disease. Most disease-causing mutations are truncating, resulting in the total absence of normal emerin protein in the nucleus; however, DCM is also triggered by emerin mutations that alter a single amino acid. An interesting example is the Val26Ala mutation. This variant was identified in several index patients in a Spanish study assessing the presence of genetic alterations in patients undergoing heart transplantation for DCM. The identified patients underwent surgery at 2 hospitals in Madrid, and all came from a Canary Island population with an established history of DCM. These patients showed no evidence of skeletal myopathy or conduction disorders, which are frequently associated with other EMD mutations. Female carriers of the variant in heterozygosis showed no signs of cardiomyopathy.33

RBM20 encodes a member of the SR protein family, named for the presence of a characteristic serine/arginine-rich domain. SR proteins regulate the alternative splicing of multiple genes, most notably TTN. The mutations in this gene identified to date are associated with autosomal dominant DCM. Most of them are missense mutations located in 2 functionally important regions, the serine/arginine-rich region (exon 9) and the zinc finger domain (exon 14), although other variants are distributed throughout the gene. Studies have revealed a poor prognosis in some patients, with high incidences of sudden cardiac death, heart failure, and heart transplantation.37,38 Other authors found no differences in survival or ventricular arrhythmia incidence between mutation carriers and noncarriers; however, the overall event rate in this study was low.39 The location of the mutation in the gene is posited to determine different disease subtypes, but this hypothesis remains unconfirmed.

FLNC encodes a cytoplasmic actin-binding protein. The first FLNC mutations identified are associated with skeletal myofibrillar myopathy, but recent data indicate that the main clinical phenotype related to FLNC mutations may be autosomal dominant cardiomyopathies. A multicenter study led by our group recently found that truncating FLNC mutations are associated with a highly penetrant overlapping phenotype between DCM and left-dominant ACM.40 The disease is characterized by almost exclusive left ventricular involvement, and notable disease features include dilatation and systolic dysfunction (sometimes mild in both cases), extensive areas of intramyocardial fibrosis in the left ventricular wall, a high frequency of ventricular arrhythmias, an absence of skeletal myopathy, and normal creatine kinase. The study found a high incidence of sudden cardiac death, especially in patients older than 40 years and even in patients with mild-to-moderate ventricular dysfunction.40 Recent evidence also links missense FLNC mutations to restrictive cardiomyopathy and HCM, although the evidence for these associations is less firm.

BAG3 encodes BAG family molecular chaperone regulator 3. This protein has antiapoptotic activity and is highly expressed in skeletal and cardiac muscle, where it is located in the Z-disc. Cardiovascular phenotypes associated with BAG3 have only recently been described clinically, and to date few mutations have been identified.41 Of the known BAG3 variants causing autosomal dominant DCM, most are exon deletions or truncating mutations, although a smaller number of disease-associated missense mutations has been identified; some of the identified mutations generate a severe phenotype.42 Some missense mutations are associated with myofibrillar myopathy, also with autosomal dominant inheritance.

PLN encodes phospholamban, a protein located in the sarcoplasmic reticulum membrane. The p.Arg14del mutation in PLN is associated with DCM and has a founder effect in the Netherlands. This variant has been linked to the development of left-dominant ACM and arrhythmic forms of autosomal dominant DCM; mutation carriers are at high risk of malignant ventricular arrhythmias and advanced heart failure in young adulthood, with the rate of ventricular arrhythmias similar to that observed for LMNA mutations.43 A low amplitude R-wave has been identified as an early disease marker in mutation carriers and correlates with late gadolinium enhancement on cardiovascular magnetic resonance. Another study found low penetrance and milder phenotypes, especially for truncating mutations.44 Other PLN variants are related to the development of HCM.

SCN5A encodes sodium voltage-gated channel alpha subunit 5, also known as Nav1.5. Most of the described mutations are associated with long QT and Brugada syndromes with an autosomal dominant inheritance pattern. Other phenotypes associated with SCN5A mutations are progressive conduction system disease (Lev-Lenègre disease), sinus node disease, and atrial fibrillation. A relatively small number of SCN5A mutations cause DCM; the best characterized is p.Arg222Gln, which cosegregates with the disease in multiple families from several countries.45 Most of the DCM-linked mutations are missense mutations located in the highly conserved transmembrane segments S3 and S4. The pathophysiological mechanism by which these variants cause DCM is unclear, but several hypotheses have been proposed.46

LAMP2 encodes a lysosomal membrane protein, and mutations in this gene cause Danon disease, also known as glycogen storage disease type IIb. Several cardiomyopathy-associated mutations have been described that manifest very differently in men and women. Male patients (hemizygotes) develop HCM in childhood, and the disease features very severe hypertrophy and early progression to systolic dysfunction. In contrast, the initial diagnosis in women is usually DCM. Patients frequently show conduction alterations and pre-excitation on electrocardiography; moreover, associations have been reported with skeletal myopathy, retinopathy, and cognitive impairment, predominantly in men.47 Men have a worse prognosis and normally die between the ages of 30 and 40 years; however, the disease is also severe in women, in whom it is the form of DCM with the worst prognosis.

Mitochondrial diseases can be caused by mutations in mitochondrial DNA and thus show matrilineal inheritance. Nevertheless, most genes involved in the maintenance of mitochondrial structure and function are located in the nuclear genome and thus show Mendelian inheritance, usually with an autosomal recessive pattern. Mitochondrial disease should be suspected in patients with central nervous system disorders and multisystem disease. One of the most prominent mitochondrial diseases associated with DCM is Barth syndrome, which is caused by mutations in TAZ. The TAZ gene product tafazzin is involved in the mitochondrial metabolism of cardiolipin. Barth syndrome manifests as cardiomyopathy (dilated, hypertrophic, or with left ventricular noncompaction), endocardial fibroelastosis, skeletal myopathy, growth delay, neutropenia, and organic aciduria. Inheritance is X-linked, and women are usually asymptomatic carriers.48

Given the phenotypic variability and incomplete penetrance observed in DCM patients sharing the same genetic alteration, it is clear that disease manifestation and prognosis can be influenced by other factors, both favorably and unfavorably. These factors include additional genetic variants, as well as environmental and epigenetic factors.

Most DCM-associated genes (LMNA, RBM20, and sarcomere genes) cause disease predominantly in men.49 Moreover, some genes are associated with marked sex differences in disease progression and prognosis.50 Such differences are easy to explain for diseases caused by X chromosome genes, such as DMD and EMD; however, for genes located on other chromosomes, these differences currently lack a satisfactory explanation.

Physical exercise is generally recommended for heart failure patients, but for specific disease etiologies it can increase the risk of arrhythmia. For carriers of desmosomal gene mutations, resistance training has been found to increase disease penetrance and progression to clinical heart failure and arrhythmias.51 In HCM patients with mutations in sarcomere genes, intense physical activity is linked to earlier diagnosis, but there are no reported major prognostic differences.52 In carriers of disease-causing LMNA mutations, participation in competitive sports increases the risk of adverse events even if the activity ceased several years before diagnosis.53

Several studies have shown an influence of other environmental factors on the expression of familial DCM. These factors include myocarditis, nutritional deficiences, and cytotoxic agents.54–56 Alchohol consumption is regarded as an important etiological factor in DCM, and recent studies have shown an elevated genetic predisposition in patients with alcoholic DCM.57