List of common genes and patterns of inheritance in DCM, modified from Tayal et al. [9].
Abstract
Cardiomyopathies (CMs) encompass a heterogeneous group of structural and functional (systolic and diastolic) abnormalities of the myocardium and are either confined to the cardiovascular system or are part of a systemic disorder. CMs represent a leading cause of morbidity and mortality and account for a significant percentage of death and cardiac transplantation. The 2006 American Heart Association (AHA) classification grouped CMs into primary (genetic, mixed, or acquired) or secondary (i.e., infiltrative or autoimmune). In 2008, the European Society of Cardiology classification proposed subgrouping CM into familial or genetic and nonfamilial or nongenetic forms. In 2013, the World Heart Federation recommended the MOGES nosology system, which incorporates a morpho-functional phenotype (M), organ(s) involved (O), the genetic inheritance pattern (G), an etiological annotation (E) including genetic defects or underlying disease/substrates, and the functional status (S) of a particular patient based on heart failure symptoms. Rapid advancements in the biology of cardio-genetics have revealed substantial genetic and phenotypic heterogeneity in myocardial disease. Given the variety of disciplines in the scientific and clinical fields, any desired classification may face challenges to obtaining consensus. Nonetheless, the heritable phenotype-based CM classification offers the possibility of a simple, clinically useful diagnostic scheme. In this chapter, we will describe the genetic basis of dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic cardiomyopathy (ACM), LV noncompaction cardiomyopathy (LVNC), and restrictive cardiomyopathy (RCM). Although the descriptive morphologies of these types of CM differ, an overlapping phenotype is frequently encountered within the CM types and arrhythmogenic pathology in clinical practice. CMs appear to originate secondary to disruption of “final common pathways.” These disruptions may have purely genetic causes. For example, single gene mutations result in dysfunctional protein synthesis causing downstream dysfunctional protein interactions at the level of the sarcomere and a CM phenotype. The sarcomere is a complex with multiple protein interactions, including thick myofilament proteins, thin myofilament proteins, and myosin-binding proteins. In addition, other proteins are involved in the surrounding architecture of the sarcomere such as the Z-disk and muscle LIM proteins. One or multiple genes can exhibit tissue-specific function, development, and physiologically regulated patterns of expression for each protein. Alternatively, multiple mutations in the same gene (compound heterozygosity) or in different genes (digenic heterozygosity) may lead to a phenotype that may be classic, more severe, or even overlapping with other disease forms.
Keywords
- Inherited cardiovascular disease
- Syndromic cardiovascular disease
- Gene variants
- Gene disorders
- Genetic syndrome
- Pathogenic mutation
- Heritable cardiomyopathy
- Sarcomeric cardiomyopathy
- Metabolic disorders
- Neuromuscular disease
1. Introduction
Cardiomyopathies (CMs) encompass a heterogeneous group of structural and functional (systolic and diastolic) abnormalities of the myocardium and are either confined to the cardiovascular system or are part of a systemic disorder. CMs represent a leading cause of morbidity and mortality and account for a significant percentage of death and cardiac transplantation [1]. The 2006 American Heart Association (AHA) classification grouped CMs into primary (genetic, mixed, or acquired) or secondary (i.e., infiltrative or autoimmune). In 2008, the European Society of Cardiology classification proposed subgrouping CM into familial or genetic and nonfamilial or nongenetic forms. In 2013, the World Heart Federation recommended the MOGES nosology system, which incorporates a morpho-functional phenotype (M), organ(s) involved (O), the genetic inheritance pattern (G), an etiological annotation (E) including genetic defects or underlying disease/substrates, and the functional status (S) of a particular patient based on heart failure symptoms [2, 3, 4]. Rapid advancements in the biology of cardio-genetics have revealed substantial genetic and phenotypic heterogeneity in myocardial disease. Given the variety of disciplines in the scientific and clinical fields, any desired classification may face challenges to obtaining consensus. Nonetheless, the heritable phenotype-based CM classification offers the possibility of a simple, clinically useful diagnostic scheme (for an example, see [5]). In this chapter, we will describe the genetic basis of dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic cardiomyopathy (ACM), LV noncompaction cardiomyopathy (LVNC), and restrictive cardiomyopathy (RCM). Although the descriptive morphologies of these types of CM differ, an overlapping phenotype is frequently encountered within the CM types and arrhythmogenic pathology in clinical practice. CMs appear to originate secondary to disruption of “final common pathways.” These disruptions may have purely genetic causes. For example, single gene mutations result in dysfunctional protein synthesis causing downstream dysfunctional protein interactions at the level of the sarcomere and a CM phenotype. The sarcomere is a complex with multiple protein interactions, including thick myofilament proteins, thin myofilament proteins, and myosin-binding proteins. In addition, other proteins are involved in the surrounding architecture of the sarcomere such as the Z-disk and muscle LIM proteins (Figure 1). One or multiple genes can exhibit tissue-specific function, development, and physiologically regulated patterns of expression for each protein. Alternatively, multiple mutations in the same gene (compound heterozygosity) or in different genes (digenic heterozygosity) may lead to a phenotype that may be classic, more severe, or even overlapping with other disease forms.
2. Heritable cardiomyopathies
2.1 Dilated cardiomyopathy
DCM is mainly characterized by left or biventricular dilatation, increased LV mass, and decreased systolic function (Figure 2) [6]. DCM can present with the clinical syndrome of systolic heart failure or with or without associated arrhythmias or thrombo-embolic disease. Additionally, DCM can be detected in asymptomatic individuals. Globally, DCM is the most common form of CM and the leading cause of heart transplantation in children and adults. The estimated incidence in the pediatric population is between 0.34 to 1.13 cases per 100,000 children per year with differences in demographic characteristics [7]. DCM has many known etiologies with many more to be discovered. Unfortunately, in many cases, no etiology can be found, and the CM is deemed idiopathic. Still, 25 to 50% of patients with idiopathic DCM have a positive family history, suggesting an underlying genetic predisposition [8]. The majority of genetically triggered cases of DCM are transmitted in an autosomal dominant pattern exhibiting variable penetrance. Other forms of inheritance include autosomal recessive, X-linked, and mitochondrial (maternally inherited), which are more frequent in the pediatric population [2]. Familial DCM occurs in 20 to 60% of cases, where approximately 40% of those cases may have a primary monogenic basis. However, this percentage is a variable approximation as a more critical evaluation of the genes linked to DCM continues to evolve and certain types of variations are excluded from being certified as pathogenic [8]. Another conventional classification of DCM is based on the presence or absence of systemic disease. Thus, dividing DCM into syndromic and non-syndromic forms is a practical approach to evaluating this highly heterogeneous disease. The diagnostic rate for gene testing in non-syndromic DCM is 46 to 73% [9], but this estimation may likely be confounded by insufficient control for population variation. Over the past decade, 47 new genes (for a total of 60 different genes) have been linked to DCM in the Human Gene Mutation Database (HGMD), see Table 1. From these genes, a large-scale analysis revealed truncating variants in the titin gene (
Gene | Protein | Pattern of Inheritance | Disease Association | OMIM# | Locus |
---|---|---|---|---|---|
ABCC9 | ATP-Binding Cassette, Subfamily C, Member 9 | AD | DCM | 601439 | 14q12-q22 |
ACTC1 | Actin, Alpha, Cardiac Muscle | AD | DCM, LVNC, ACM, HCM | 102540 | 5q31.1 |
ACTN2 | Actinin, Alpha-2 | AD | DCM, HCM | 102573 | 6q22.1 |
AKAP9 | A-Kinase Anchor Protein 9 | AD | DCM | 604001 | 2q32.1-q32.3 |
ALMS1 | Centrosome and Basal Body Associated Protein | AR | DCM | 606844 | 10p14-p12 |
ALPK3 | Alpha Kinase 3 | AR | DCM, HCM | 617608 | 1p36.32 |
ANKRD1 | Ankyrin Repeat Domain-Containing Protein 1 | AD | DCM, HCM | 609599 | 7q36.1 |
BAG3 | Bcl2-Associated Athanogene 3 | AD | DCM, RCM, HCM | 603883 | 14q24.3 |
CASQ2 | Calsequestrin 2 | AR, AD | DCM, LVNC | 114251 | 6q22.31 |
CAV3 | Caveolin 3 | AD | DCM, HCM | 601253 | 12q24.13 |
CHRM2 | Cholinergic Receptor, Muscarinic, 2 | AD | DCM | 118493 | 10q25.2-q26.2 |
CRYAB | Crystallin, Alpha-B | AD | DCM | 123590 | 11q23.1 |
CSRP3 | Cysteine- And Glycine-Rich Protein 3 | AD | DCM, HCM | 600824 | 12p12.1 |
CTF1 | Cardiotrophin 1 | AR, AD | DCM | 600435 | 1p13.1 |
DES | Desmin | AD,AR | DCM, ACM, RCM | 125660 | 17q21 |
DMD | Dystrophin | XL | DCM | 300377 | 3p25.3 |
DOLK | Dolichol Kinase | AR | DCM | 610746 | 7q33 |
DSC2 | Desmocollin 2 | AD, AR | DCM, ACM | 600271 | Xq22 |
DSG2 | Desmoglein 2 | AD | DCM, ACM | 125671 | 15q24.1 |
DSP | Desmoplakin | AD, AR | DCM, ACM | 125485 | 11p15.5 |
DTNA | Dystrobrevin Alpha | AD | DCM, LVNC | 601239 | 2q31 |
EMD | Emerin | XL | DCM | 300384 | 11q23.1 |
EYA4 | Eyes Absent, Drosophila, Homolog Of, 4 | AD | DCM | 603550 | 11p15.1 |
FHL1 | Four-And-A-Half LIM Domains 1 | XL | DCM, HCM | 300163 | 15q22.31 |
FHL2 | Four-And-A-Half LIM Domains 2 | Unknown | DCM | 602633 | 16p11.2 |
FKRP | Fukutin-Related Protein | AR | DCM | 606596 | 10q21.3 |
FKTN | Fukutin | AR | DCM | 607440 | 2q35 |
FLNC | Filamin C | AD | DMC, RCM, HCM, ACM | 102565 | 10q22.2 |
GATA4 | Gata-Binding Protein 4 | AD | DCM | 600576 | Xq21.2-p21.1 |
GATAD1 | Gata Zinc Finger Domain-Containing Protein 1 | AR | DCM | 614518 | 9q34.11 |
GLA | Galactosidase, Alpha | XL | DCM, HCM | 300644 | 18q11.2 |
ILK | Integrin-Linked Kinase | AD | DCM | 602366 | 18q12.1 |
JUP | Junction Plakoglobin | AD, AR | DCM, ACM | 173325 | 2p13.1 |
LAMA4 | Laminin, Alpha-4 | AD | DCM | 600133 | 18q12.1 |
LAMP2 | Lysosome-Associated Membrane Protein 2 | XL | DCM, HCM | 309060 | 3p25.2 |
LDB3 | Lim Domain-Binding 3 | AD | DCM, LVNC, ACM, HCM | 605906 | 2p22.1 |
LMNA | Lamin A/C | AD, AR | DCM, LVNC, ACM, HCM | 150330 | 1q22 |
LRRC10 | Leucine-Rich Repeat-Containing Protein 10 | AD, AR | DCM | 610846 | 4q21.3 |
MURC/CAVIN4 | Muscle-Related Coiled-Coil Protein/Caveolae-Associated Protein 4 | AD | DCM | 617714 | 18q12.1 |
MYBPC3 | Myosin-Binding Protein C, Cardiac | AD | DCM, LVNC, RCM, HCM | 600958 | Xq28 |
MYH6 | Myosin, Heavy Chain 6, Cardiac Muscle, Alpha | AD | DCM, HCM | 160710 | 10q25.2 |
MYH7 | Myosin, Heavy Chain 7, Cardiac Muscle, Beta | AD | DCM, LVNC, RCM, HCM | 160760 | 7p14.2 |
MYL2 | Myosin, Light Chain 2, Regulatory, Cardiac, Slow | AD | DCM, HCM | 160781 | 3p21.3-p21.2 |
MYL3 | Myosin, Light Chain 3, Alkali, Ventricular, Skeletal, Slow | AD, AR | DCM, HCM, RCM | 160790 | 1q32 |
MYLK2 | Myosin Light Chain Kinase 2 | AD | DCM, HCM | 606566 | 20q13.31 |
MYOT | Myotilin | AD | DCM | 604103 | Xq28 |
MYOZ2 | Myozenin 2 | AD | DCM, RCM, HCM | 605602 | 3p25.1 |
MYPN | Myopalladin | AD | DCM, RCM, HCM | 608517 | 12q23.1 |
NEBL | Nebulette | AD | DCM | 605491 | 6q23.2 |
NEXN | Nexilin (F Actin Binding Protein) | AD | DCM, HCM | 613121 | 1q22 |
NKX2-5 | Nk2 Homeobox 5 | AD | DCM | 600584 | Xq26.3 |
PDLIM3 | Pdz And Lim Domain Protein 3 | AD | DCM, HCM | 605899 | 1q43 |
PKP2 | Plakophilin 2 | AD | DCM, ACM | 602861 | 11p15.4 |
PLN | Phospholamban | AD | DCM, ACM, HCM | 172405 | 4q12 |
PRDM16 | Pr Domain-Containing Protein 16 | AD | DCM, LVNC | 605557 | 6q21 |
PRKAG2 | Protein Kinase, Amp-Activated, Noncatalytic, Gamma-2 | AD | DCM, HCM | 602743 | 4q26-q27 |
RBM20 | RNA-Binding Motif Protein 20 | AD | DCM | 613171 | 2q12.2 |
RYR2 | Ryanodine Receptor 2 (Cardiac) | AD | DCM, HCM, ACM | 180902 | 12p11 |
SCN5A | Sodium Channel, Voltage-Gated, Type V, Alpha Subunit | AD | DCM, ACM | 600163 | 20q13.12 |
SGCA | Sarcoglycan Alpha | AR | DCM | 600119 | 1q25.2 |
SGCB | Sarcoglycan Beta | AR | DCM | 600900 | 15q22.1 |
SGCD | Sarcoglycan, Delta (35kda Dystrophin-Associated Glycoprotein) | AD, AR | DCM | 601411 | 19q13.32 |
SLC25A4 | Solute Carrier Family 25, Member 4 (Mitochondrial Carrier Adenine Nucleotide Translocator) | AD, AR | DCM | 103220 | 7q21-q22 |
TAZ | Tafazzin | AR, XL | DCM, LVNC | 300394 | Xq24 |
TBX20 | T-Box 20 | AD | DCM, LVNC | 606061 | 10q22.3-q23.2 |
TCAP | Titin-Cap (Telethonin) | AR | DCM, HCM | 604488 | 3p21 |
TMEM43 | Transmembrane Protein 43 | AD | DCM, ACM | 612048 | 10q23.3 |
TMPO | Thymopoietin | AD | DCM | 188380 | 9q31.2 |
TNNC1 | Troponin C Type 1 (Slow) | AD | DCM, HCM | 191040 | 17q21.33 |
TNNI3 | Troponin I Type 3 (Cardiac) | AD | DCM, RCM, HCM | 191044 | 3p21.1 |
TNNT2 | Troponin T Type 2 (Cardiac) | AD | DCM, LVNC, RCM, HCM | 191045 | 17q12 |
TOR1AIP1 | Torsin-1a-Interacting Protein 1 | AR | DCM | 614512 | 7q32.1 |
TPM1 | Tropomyosin 1 (Alpha) | AD | DCM, RCM, HCM | 191010 | 19q13.4 |
TRDN | Triadin | AR | DCM | 603283 | 17q25.3 |
TTN | Titin | AD, AR | DCM, ACM, HCM | 188840 | 5q33-q34 |
TTR | DCM | AD | DCM | 176300 | 18q12.1 |
TXNRD2 | Thioredoxin Reductase 2 | AD, AR | DCM | 606448 | 8p23.1 |
VCL | Vinculin | AD | DCM, LVNC, HCM | 193065 | 10q25.2 |
Regardless of the mode of inheritance, pathogenic gene variants result in a cardiomyocyte milieu susceptible to stress, leading to downstream dysfunction of the contractile apparatus and heart failure, “the final common pathway” hypothesis [14]. The term “familial DCM” is frequently applied in the presence of DCM in two or more first-degree relatives. The incidence is likely underestimated due to the diversity of inheritance patterns, timing of presentation, variable penetrance, and lack of symptoms in subclinical disease [15, 16].
2.1.1 Autosomal dominant dilated cardiomyopathy
The most common form of familial DCM is inherited in an autosomal dominant pattern [6]. In this sub-type, arrhythmias associated with DCM (DCM-A) are frequently encountered [17]. Genetic heterogeneity exists with at least 30 unique genes identified in familial non-arrhythmogenic DCM and five genes for DCM-A [17, 18].
2.1.2 X-linked Cardiomyopathy (XLCM)
XLCM has been reported as an isolated disease of the heart or associated with skeletal myopathy such as with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD). All skeletal myopathies are frequently associated with the development of DCM and/or DCM-A. The causative gene codes for the protein dystrophin located at the short arm of the X chromosome at Xp21. Dystrophin is a cytoskeletal protein that provides structural support to the cardiomyocyte and plays a major role in linking the sarcomeric contractile apparatus to the sarcolemma and extracellular matrix (ECM) [19, 20]. DMD and BMD are severe muscular dystrophies of childhood, affecting ~1 in 3,500 males for DMD and 1 in 300,000 males for BMD. Typically, DMD and BMD are characterized by skeletal myopathy, elevated serum creatine kinase, and calf pseudo-hypertrophy. DMD is the more severe form due to the absence of functional dystrophin, leading to muscle weakness by 3 years of age and wheelchair dependence by 12 years of age [21]. Cardiac involvement varies with age but is nearly universal by 20 years in all DMD patients. The onset of clinical features starts later in life in BMD than in DMD. Histologic studies show cardiac muscle replacement with fibrosis. This fibrosis eventually leads to ventricular dysfunction/enlargement and is associated with conduction system abnormalities and ventricular arrhythmias. Molecular analysis of the
2.1.3 Isolated X-Linked Dilated Cardiomyopathy
Isolated XLCM is characterized by consistent early expression and rapid progression of CM in males during childhood, later onset with slower progression in females, and no male-to-male transmission [26]. Linkage analysis of X-chromosome-specific DNA markers performed in suspected individuals demonstrated preferential involvement of cardiac muscle and normal dystrophin by Western blotting in skeletal muscle of the same affected individuals [27]. The phenotype and pathologic features described in this population do not differ from those in patients with DCM. Hence, the medical management should be provided according to the current heart failure guidelines.
2.1.4 Emery-Dreifuss Muscular Dystrophy
Emery-Dreifuss muscular dystrophy (EDMD), also known as humeroperoneal muscular dystrophy, is a heterogeneous disorder with X-linked recessive, autosomal dominant, and autosomal recessive forms of inheritance [28]. Several forms of this disease are considered nuclear envelopathies because they are associated with mutations in genes encoding nuclear membrane proteins, including the
2.1.5 Barth Syndrome
Barth syndrome (BTS) is another X-linked cardioskeletal myopathy that encompasses abnormal mitochondrial function, short stature, cyclic neutropenia, cardiolipin deficiency, and variable degrees of 3-methylglutaconic aciduria. BTS is caused by mutations in the
2.2 Hypertrophic cardiomyopathy
HCM is the second most prevalent CM in children, representing 40% of cases, with an estimated incidence of 0.47 in 100,000 children [35]. HCM is more prevalent in boys than in girls and in African American children than in Caucasian or Hispanic children. In the pediatric population, the incidence of HCM is 10 times higher in patients under 1 year of age than in older children [36]. HCM is a primary myocardial disorder with mainly an autosomal dominant pattern of inheritance characterized by hypertrophy of the left ventricle (with or without hypertrophy of the right ventricle) and histologic features of myocyte hypertrophy, myofibrillar disarray, and interstitial fibrosis. While asymmetric septal hypertrophy is the most common pattern of hypertrophy, the degree and location of hypertrophy vary. Some patients exhibit concentric hypertrophy, harbored in other walls or confined to the left ventricular apex (Figure 3) [37].
The clinical presentation of HCM is highly variable, ranging from asymptomatic hypertrophy, to symptomatic arrhythmias, to refractory heart failure due to diastolic dysfunction, or “burned-out HCM” with the development of systolic dysfunction. Notably, diastolic dysfunction can even be detected in individuals with HCM who have normal LV wall thickness, suggesting that diastolic dysfunction is an early feature of HCM rather than a secondary consequence of hypertrophy [38]. Categorization of HCM includes non-syndromic HCM (without other systemic involvement) and the syndromic form of HCM (in association with inborn errors of metabolism, malformation syndromes, and neuromuscular disorders) [39].
Approximately 20–30% of individuals with non-syndromic HCM and no family history of HCM harbor a pathogenic variant in a known gene encoding a component of the sarcomere. However, 50–60% of adults and children with a positive family history of HCM harbor a pathogenic gene variant. Furthermore, 3–5% of affected individuals have more than one sarcomere gene variant (either biallelic variants in 1 gene or heterozygous variants in >1 gene) [40, 41].
2.2.1 Non-syndromic Hypertrophic Cardiomyopathy
More than two decades ago, the first chromosome locus (14q11.2-q12) encoding components of the sarcomere (beta-myosin heavy chain) was elucidated as the pathogenic basis for familial HCM [42]. Since then, more than 1,400 mutations in 27 identified genes have been associated with HCM, see Table 2 [43]. The vast majority have autosomal dominant transmission, but mitochondrial and autosomal recessive patterns have been also described [44, 45, 46]. Most of the disease-causing mutations implicated in HCM include mutations in the
Gene | Protein | Pattern of Inheritance | Disease Association | OMIM# | Locus |
---|---|---|---|---|---|
ACTC1 | Actin, Alpha, Cardiac Muscle | AD | HCM, DCM, LVNC, ACM | 102540 | 5q31.1 |
ACTN2 | Actinin, Alpha-2 | AD | HCM, DCM | 102573 | 6q22.1 |
ALPK3 | Alpha Kinase 3 | AR | HCM, DCM | 617608 | 1p36.32 |
ANKRD1 | Ankyrin Repeat Domain-Containing Protein 1 | AD | HCM, DCM | 609599 | 7q36.1 |
BAG3 | Bcl2-Associated Athanogene 3 | AD | HCM, DCM, RCM | 603883 | 14q24.3 |
BRAF | V-Raf Murine Sarcoma Viral Oncogene Homolog B1 | AD | HCM | 164757 | 12q15 |
CAV3 | Caveolin 3 | AD | HCM, DCM | 601253 | 12q24.13 |
CSRP3 | Cysteine- And Glycine-Rich Protein 3 | AD | HCM, DCM | 600824 | 12p12.1 |
FHL1 | Four-And-A-Half LIM Domains 1 | XL | HCM | 300163 | 15q22.31 |
FLNC | Filamin C | AD | HCM, ACM, DMC, RCM | 102565 | 10q22.2 |
GAA | Glucosidase, Alpha, Acid | AR | HCM | 606800 | 19p13.3 |
GLA | Galactosidase, Alpha | XL | HCM | 300644 | 18q11.2 |
HRAS | V-Ha-Ras Harvey Rat Sarcoma Viral Oncogene Homolog | AD | HCM | 190020 | 9q31.1 |
JPH2 | Junctophilin 2 | AD | HCM | 605267 | 11p11.2 |
KRAS | V-Ki-Ras2 | AD | HCM | 190070 | 14q12 |
LAMP2 | Lysosome-Associated Membrane Protein 2 | XL | HCM, DCM | 309060 | 3p25.2 |
LDB3 | Lim Domain-Binding 3 | AD | HCM, DCM, LVNC, ACM | 605906 | 2p22.1 |
LMNA | Lamin A/C | AD, AR | HCM, DCM, LVNC, ACM | 150330 | 1q22 |
MAP2K1 | Mitogen-Activated Protein Kinase Kinase 1 | AD | HCM | 176872 | 14q12 |
MAP2K2 | Mitogen-Activated Protein Kinase Kinase 2 | AD | HCM | 601263 | 12q24.11 |
MYBPC3 | Myosin-Binding Protein C, Cardiac | AD | HCM, DCM, LVNC, RCM | 600958 | Xq28 |
MYH6 | Myosin, Heavy Chain 6, Cardiac Muscle, Alpha | AD | HCM, DCM | 160710 | 10q25.2 |
MYH7 | Myosin, Heavy Chain 7, Cardiac Muscle, Beta | AD | HCM, DCM, LVNC, RCM | 160760 | 7p14.2 |
MYL2 | Myosin, Light Chain 2, Regulatory, Cardiac, Slow | AD | HCM | 160781 | 3p21.3-p21.2 |
MYL3 | Myosin, Light Chain 3, Alkali, Ventricular, Skeletal, Slow | AD, AR | HCM, RCM | 160790 | 1q32 |
MYLK2 | Myosin Light Chain Kinase 2 | AD | HCM | 606566 | 20q13.31 |
MYOM1 | Myomesin 1 | AD | HCM | 603508 | 18p11.31 |
MYOZ2 | Myozenin 2 | AD | HCM, DCM, RCM | 605602 | 3p25.1 |
MYPN | Myopalladin | AD | HCM, DCM, RCM | 608517 | 12q23.1 |
NEXN | Nexilin (F Actin Binding Protein) | AD | HCM, DCM | 613121 | 1q22 |
NRAS | Neuroblastoma Ras Viral Oncogene Homolog | AD | HCM | 164790 | 5q31.2 |
PDLIM3 | Pdz And Lim Domain Protein 3 | AD | HCM, DCM | 605899 | 1q43 |
PLN | Phospholamban | AD | HCM, DCM, ACM | 172405 | 4q12 |
PRKAG2 | Protein Kinase, Amp-Activated, Noncatalytic, Gamma-2 | AD | HCM | 602743 | 4q26-q27 |
PTPN11 | Protein-Tyrosine Phosphatase, Nonreceptor-Type, 11 | AD | HCM | 176876 | 10q21.3 |
RAF1 | V-Raf-1 Murine Leukemia Viral Oncogene Homolog 1 | AD | HCM | 164760 | 10p12 |
RIT1 | Ras-Like Without Caax 1 | AD | HCM | 609591 | 1p31.1 |
RYR2 | Ryanodine Receptor 2 (Cardiac) | AD | HCM, ACM | 180902 | 12p11 |
SHOC2 | Soc-2 Homolog | AD | HCM | 602775 | 5q35.1 |
SOS1 | Son Of Sevenless, Drosophila, Homolog 1 | AD | HCM | 182530 | 1p13.2 |
TCAP | Titin-Cap (Telethonin) | AR | HCM, DCM | 604488 | 3p21 |
TNNC1 | Troponin C Type 1 (Slow) | AD | HCM, DCM | 191040 | 17q21.33 |
TNNI3 | Troponin I Type 3 (Cardiac) | AD | HCM, DCM, RCM | 191044 | 3p21.1 |
TNNT2 | Troponin T Type 2 (Cardiac) | AD | HCM, DCM, LVNC, RCM | 191045 | 17q12 |
TPM1 | Tropomyosin 1 (Alpha) | AD | HCM, DCM, RCM | 191010 | 19q13.4 |
TTN | Titin | AD, AR | HCM, DCM, ACM | 188840 | 5q33-q34 |
TTR | Transthyretin | AD | HCM | 176300 | 4q35.1 |
VCL | Vinculin | AD | HCM, DCM, LVNC | 193065 | 10q25.2 |
Mouse models of sarcomeric mutations have shown changes in cardiac chemistry and diastolic function well before myocardial hypertrophy is observed [48]. Moreover, the genetic defect in a gene encoding for a sarcomeric protein may disrupt normal contraction and relaxation with dysregulation of calcium in the sarcomere. Thus, reduced calcium reuptake and decreased stores in the sarcoplasmic reticulum will trigger a remodeling process by several transcription factors, resulting in the hypertrophy of the cardiomyocytes and increased energy demand, which eventually results in ischemia, fibrosis, and death [44]. There is no reliable correlation between the genotype and phenotype among the identified sarcomeric mutations, except for those patients harboring multiple mutations [49].
2.2.2 Syndromic hypertrophic cardiomyopathy
HCM has been associated with multiple phenotypically distinct disorders. Improvements in sequencing technologies and phenotypic characterization and the incorporation of epigenetics have expanded our understanding of syndromic CMs.
2.2.2.1 RAS/MAPK pathway syndromes
Since the discovery of the first gene (
The management of RASopathies should involve a multidisciplinary team with expertise in the assessment of cardiac structural defects, HCM, and arrhythmias. Surveillance with periodic echocardiography (HCM), electrocardiography (rhythm disturbances), neurologic and eye examination, evaluation for scoliosis, and assessment of growth and cognitive development is also recommended.
2.2.2.1.1 Noonan syndrome
Noonan syndrome is relatively common with a prevalence of ~1 in 3500 people. This disease is inherited in an autosomal dominant pattern, although new cases are common because the
Surgical relief of right ventricular outflow tract obstruction (RVOTO) is recommended in patients with more than a mild degree of obstruction. Septal myectomy is also advised when left ventricular outflow tract obstruction (LVOTO) is associated with heart failure symptoms, although re-growth of the LVOTO is common when myectomy is performed in patients younger than one year of age. In some children, heart transplantation is necessary.
2.2.2.1.2 LEOPARD syndrome
LEOPARD syndrome, also called Noonan syndrome with multiple lentigines, is a rare autosomal dominant disorder caused by mutations in the protein tyrosine phosphatase gene,
2.2.2.1.3 Costello syndrome
Costello syndrome is a rare disorder with substantial clinical overlap with other RASopathy syndromes. This disorder is caused by mainly
2.2.2.1.4 Cardiofaciocutaneous (CFC) syndrome
Cardiofaciocutaneous (CFC) syndrome also has substantial clinical overlap with other RASopathy syndromes because of its common ectodermal involvement as well as findings of intellectual impairment and cardiac anomalies. Skin abnormalities can be extensive and include hyperkeratosis, eczema, palmoplantar hyperkeratosis, and keratosis pilaris. The hair is typically sparse and curly. CFC syndrome is characterized by cardiac abnormalities (pulmonary valve stenosis, other valve dysplasias, septal defects, HCM, and rhythm disturbances). HCM is identified in approximately 40% of cases and presents more commonly during infancy, but it can develop at any age [59]. Neoplasia, mostly acute lymphoblastic leukemia (ALL), has been reported in some individuals [50, 60]. Diagnosis is based on clinical findings and molecular genetic testing. Common genes associated with CFC syndrome include
2.2.2.2 Metabolic disorders associated with cardiomyopathy
Congenital metabolic disorders result from absent or abnormal enzymes—or their cofactors—which can lead to accumulation or deficiency of a specific metabolite. Although these disorders exhibit different modes of inheritance, most are transmitted in an autosomal recessive or mitochondrial pattern. The possibility of an inborn error of metabolism should be considered in infants, children, and young adults who present with any of the cardiovascular phenotypes or laboratory features described below. Optimal outcomes for children with these disorders depend upon early recognition of the signs and symptoms of metabolic disease, prompt evaluation, and referral to a center with expertise in cardiovascular genetics. Delay in diagnosis may result in acute metabolic/hemodynamic decompensation, progressive neurologic injury, or death.
2.2.2.2.1 Pompe disease
Pompe disease, also known as glycogen storage disease type II, is an autosomal recessive metabolic disorder that affects muscle and nerve cells throughout the body. This condition occurs secondary to accumulation of glycogen in lysosomes due to a deficiency of the lysosomal acid alpha-glucosidase enzyme. The build-up of glycogen leads to progressive myopathy and weakness throughout the body affecting various tissues including the liver, nervous system, and—most notably—skeletal muscle and myocardium. The Pompe phenotype varies widely [64]. In the infantile form, muscles appear normal but are limp and weak, preventing normal development. Elevated creatine kinase, lactate dehydrogenase, and aspartate aminotransferase (AST) are common. ECG reveals a short PR interval with giant QRS complexes in all leads, suggesting biventricular hypertrophy. As the disease progresses, HCM may result in cardiorespiratory failure. Without treatment, death usually occurs due to heart failure and respiratory weakness within the first year of life [65]. The juvenile and adult forms present with a variable age of onset. The primary clinical finding is skeletal myopathy with a more protracted course, leading to respiratory failure. Affected children usually present with delayed gross-motor development and progressive weakness in a limb-girdle distribution. Early involvement of the diaphragm is a common feature leading to death in the second or third decade of life. In contrast to the infantile form, mild and non-specific cardiac abnormalities can be detected in patients with late-onset disease [66]. Enzyme replacement therapy usually results in decreased ventricular hypertrophy, reduced LV outflow tract obstruction, and normalization of the conduction system [67].
2.2.2.2.2 Danon disease
Danon disease, also known as glycogen storage disease type IIb, is an X-linked lysosomal and glycogen storage disorder associated with skeletal muscle weakness and intellectual disability. Danon disease involves a genetic defect in the
2.2.2.2.3 Fabry disease
Fabry disease is considered the most prevalent lysosomal storage disorder. This disease is an X-linked inborn error of the glycosphingolipid metabolic pathway and involves deficiency of the lysosomal hydrolase alpha-galactosidase A (alpha-Gal A) mapped to the long arm of the X chromosome (Xq22.1) [72]. Several hundred mutations in the
2.2.2.2.4 Friedreich’s ataxia
Friedreich’s ataxia is an autosomal recessive inherited disease with an estimated incidence of 1 in 50,000 in the general population. The genotype is characterized by trinucleotide repeat expansion of a normal codon affecting the protein frataxin, a mitochondrial inner membrane protein important for iron homeostasis. As the defect lies within an intron (which is removed from the mRNA transcript between transcription and translation), this mutation does not result in the production of abnormal frataxin. Instead, the mutation decreases the transcription of the gene through gene silencing. Low frataxin levels lead to insufficient biosynthesis of iron–sulfur clusters that are required for the mitochondrial electron transport chain to ultimately generate adenosine triphosphate (ATP). The major clinical manifestations of Friedreich’s ataxia include progressive neurologic dysfunction (gait ataxia, optic atrophy, loss of position and vibration sense), diabetes mellitus, and myocardial involvement. The cardiac phenotype is manifested by arrhythmias and HCM. Heart failure remains the leading cause of death in this population [77, 78]. HCM is seen in approximately two-thirds of patients with Friedreich’s ataxia, and one-third of those cases develop during childhood [79].
2.2.2.2.5 Mitochondrial cardiomyopathy
Mitochondria are the main energy source in cells due to the ability to perform oxidative phosphorylation via proteins in the mitochondrial respiratory chain. Several genes are involved in the role of cellular energy production. Mutations in these genes may result in severe involvement in organs that are heavily dependent on energy production, such as the brain, heart, and skeletal muscle. Mitochondrial DNA (mtDNA) is exclusively maternally inherited, whereas nuclear DNA follows Mendelian inheritance. The frequency of cardiac involvement in mitochondrial disease is 17–40%, and the estimated prevalence of inherited mitochondrial disease is at least 1 in 5,000 births [80]. More than 40 different types of mitochondrial disease have been associated with the development of HCM. Many forms of mitochondrial disease associated with HCM present during infancy. Because diagnosing mitochondrial disease can be challenging for clinicians, it is recommended that a multidisciplinary team (including a geneticist or mitochondrial specialist) be involved in the diagnosis and management [81]. Mitochondrial CM is characterized by abnormal heart-muscle structure, function, or both. These abnormalities result from genetic defects involving mitochondrial activity in the absence of concomitant coronary artery disease, hypertension, valvular disease, or CHD. The typical cardiac manifestations of mitochondrial disease include the presence of arrhythmias, hypertrophic HCM, LVNC and DCM. Worsening cardiovascular disease may occur during a metabolic crisis [80, 81, 82].
Barth syndrome, described earlier in this chapter, is an X-linked disorder caused by pathogenic variants in the
2.2.2.2.6 MELAS
MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) is a multisystem clinical syndrome. Cardiac involvement is manifested by nonobstructive concentric hypertrophy (HCM), although DCM, Wolff-Parkinson-White (WPW) syndrome, and atrial tachycardia have also been reported [83, 84, 85]. Several genes have been postulated to cause MELAS, including the ones listed in Table 3.
Gene/locus | Gene location |
---|---|
Mitochondrial | |
Mitochondrial | |
Mitochondrial | |
Mitochondrial | |
Mitochondrial | |
Mitochondrial | |
Mitochondrial | |
Mitochondrial | |
Mitochondrial | |
Mitochondrial |
2.3 Left ventricular noncompaction cardiomyopathy
LVNC is characterized by the presence of trabeculations, deep intertrabecular recesses, and a thin compacted myocardial layer in the left, right, or both ventricles. The incidence of LVNC is unknown, but some studies estimate 0.014% to 1.3% in the general population [4]. However, with improved echocardiographic and cardiac MRI quality and increasing awareness of LVNC in recent years, the incidence is likely underestimated [34]. Clinically, nine forms of LVNC have been described as follows: [1] the “benign” form of LVNC with normal systolic function, normal chamber sizes and thickness, and no history of arrhythmias; [2] the arrhythmogenic form of LVNC; [3] the DCM form of LVNC; [4] the HCM form of LVNC; [5] the mixed/undulating CM form of LVNC; [6] the RCM form of LVNC; [7] the biventricular noncompaction CM form; [8] the right ventricular noncompaction form (RVNC); and [9] LVNC associated with congenital heart disease [34, 81, 86, 87]. The various phenotypes are depicted in Figure 4. The clinical presentation may range from asymptomatic to a severe course accompanied by heart failure requiring heart transplant, arrhythmias, sudden cardiac death, and thromboembolic phenomena [88]. Familial cases are well-documented, and autosomal dominant transmission is the most common inheritance pattern (with variable penetrance and phenotypic heterogeneity). Other modes of inheritance include X-linked, autosomal recessive, and mitochondrial [43]. In pediatric and adult cohorts, the diagnostic rate of gene testing in patients with LVNC ranges from 17–41% depending on patient selection and the number of genes screened. An estimated 18 to 50% of probands have a family member with LVNC [89, 90]. One of the first genetic causes of isolated LVNC was described in 1997 in the gene
Gene | Protein | Pattern of Inheritance | Disease Association | OMIM# | Locus |
---|---|---|---|---|---|
ACTC1 | Actin, Alpha, Cardiac Muscle | AD | LVNC, ACM, HCM, DCM | 102540 | 5q31.1 |
CASQ2 | Calsequestrin 2 | AR, AD | LVNC | 114251 | 6q22.31 |
DTNA | Dystrobrevin, Alpha | AD | LVNC | 601239 | 2q31 |
HCN4 | Hyperpolarization-Activated Cyclic Nucleotide-Gated Potassium Channel 4 | AD | LVNC | 605206 | 18q12.1 |
LDB3 | Lim Domain-Binding 3 | AD | LVNC, ACM, HCM, DCM | 605906 | 2p22.1 |
LMNA | Lamin A/C | AD, AR | LVNC, ACM, HCM, DCM | 150330 | 1q22 |
MIB1 | E3 Ubiquitin Protein Ligase 1 | AD | LVNC | 608677 | 22q11.21 |
MYBPC3 | Myosin-Binding Protein C, Cardiac | AD | LVNC, RCM, HCM, DCM | 600958 | Xq28 |
MYH7 | Myosin, Heavy Chain 7, Cardiac Muscle, Beta | AD | LVNC, RCM, HCM, DCM | 160760 | 7p14.2 |
PRDM16 | Pr Domain-Containing Protein 16 | AD | LVNC, DCM | 605557 | 6q21 |
TAZ | Tafazzin | AR, XL | LVNC, DCM | 300394 | Xq24 |
TBX20 | T-Box 20 | AD | LVNC, DCM | 606061 | 10q22.3-q23.2 |
TNNT2 | Troponin T Type 2 (Cardiac) | AD | LVNC, RCM, HCM, DCM | 191045 | 17q12 |
VCL | Vinculin | AD | LVNC, HCM, DCM | 193065 | 10q25.2 |
Additionally, LVNC has been associated with several genetic syndromes and inborn errors of metabolism such as Coffin-Lowry syndrome, Sotos syndrome, Charcot–Marie–Tooth disease, Noonan syndrome, and BTS [100, 101, 102, 103]. A recent study also demonstrated a higher prevalence of LVNC among patients with heterotaxy than among the general population, suggesting possible common genetic mechanisms [104].
2.4 Arrhythmogenic Cardiomyopathy (ACM)
This CM is an arrhythmogenic myocardial disorder not explained by ischemia, hypertension, or valvular heart disease. ACM was previously referred to as arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD, ARVC). The reported prevalence of ACM is as common as 1 in 1,000-5,000 people [105]. The clinical diagnosis may be supported by evidence of conduction disease, supraventricular arrhythmias, and/or ventricular arrhythmias originating from any cardiac structure. ECG abnormalities include right bundle branch block pattern, an epsilon wave (defined as a low-amplitude deflection located between the end of the QRS and the onset of the T wave in leads V1–V3), and T wave inversion(s) recorded in leads V1–V4. Classically, the RV is dilated and contains fibro-fatty infiltration of the myocardium. The left ventricle is overtly affected with less frequent involvement. Notably, ACM clinically overlaps with other CM types, particularly DCM. However, ACM is distinct in that it is marked by arrhythmia at presentation with or without biventricular dilation and/or impaired systolic function [106]. This heritable disorder is usually transmitted in an autosomal dominant pattern (with variable penetrance), although autosomal recessive patterns reportedly affect junctional plakoglobin (JUP) and desmoplakin (DSP) in families with cardiocutaneous disease from Greece, Italy, India, Ecuador, Israel, and Turkey [107]. The most notable autosomal recessive diseases include Naxos disease (a homozygous pathogenic variant in the gene encoding the protein plakoglobin characterized by ACM, a non-epidermolytic palmoplantar keratoderma, and wooly hair) and Carvajal syndrome (caused by a homozygous pathogenic gene variant that truncates the DSP protein) [107, 108]. Analysis of first- and second-degree relatives of patients with ACM suggest that up to 50% of ACM cases are familial [109]. Pathogenic gene variants within the desmosomal proteins are the main cause of “classic” ACM [110]. Pathogenic gene variants in the three main classes of desmosomal proteins account for 60% of affected patients [111]. Overall, the three groups of desmosomal proteins include transmembrane desmosomal cadherins (including DSC2 and DSG2), DSP (a plakin family protein that attaches directly to the intermediate filament desmin in the myocardium), and linker proteins such as armadillo family proteins (including JUP and PKP2 that mediate interactions between the desmosomal cadherin tails and DSP) [112]. Pathogenic variants in the
Gene | Protein | Pattern of Inheritance | Disease Association | OMIM# | Locus |
---|---|---|---|---|---|
ACTC1 | Actin, Alpha, Cardiac Muscle | AD | ACM, HCM, DCM, LVNC | 102540 | 5q31.1 |
ARVD3 | Arrhythmogenic Right Ventricular Dysplasia, Familial, 3 | AD | ACM | 602086 | 12p12.1 |
ARVD4 | Arrhythmogenic Right Ventricular Dysplasia, Familial, 4 | AD | ACM | 602087 | 15q14 |
ARVD6 | Arrhythmogenic Right Ventricular Dysplasia, Familial, 6 | AD | ACM | 604401 | 1q42-q43 |
CTNNA3 | Catenin Alpha 3 | AD | ACM | 607667 | 7q21.2 |
DES | Desmin | AD,AR | ACM, RCM, DCM | 125660 | 17q21 |
DSC2 | Desmocollin 2 | AD, AR | ACM, DCM | 600271 | Xq22 |
DSG2 | Desmoglein 2 | AD | ACM, DCM | 125671 | 15q24.1 |
DSP | Desmoplakin | AD, AR | ACM, DCM | 125485 | 11p15.5 |
FLNC | Filamin C | AD | ACM, DMC, RCM, HCM | 102565 | 10q22.2 |
JUP | Junction Plakoglobin | AD, AR | ACM | 173325 | 2p13.1 |
LDB3 | Lim Domain-Binding 3 | AD | ACM, HCM, DCM, LVNC | 605906 | 2p22.1 |
LMNA | Lamin A/C | AD, AR | ACM, HCM, DCM, LVNC | 150330 | 1q22 |
PKP2 | Plakophilin 2 | AD | ACM, DCM | 602861 | 11p15.4 |
PLN | Phospholamban | AD | ACM, HCM, DCM | 172405 | 4q12 |
RYR2 | Ryanodine Receptor 2 (Cardiac) | AD | ACM, HCM | 180902 | 12p11 |
SCN5A | Sodium Channel, Voltage-Gated, Type V, Alpha Subunit | AD | ACM, DCM | 600163 | 20q13.12 |
TGFB3 | Transforming Growth Factor Beta 3 | AD | ACM | 190230 | |
TMEM43 | Transmembrane Protein 43 | AD | ACM | 612048 | 10q23.3 |
TTN | Titin | AD, AR | ACM, HCM, DCM | 188840 | 5q33-q34 |
2.5 Restrictive cardiomyopathy (RCM)
RCM is rare, accounting for approximately 5% of all CMs. RCM is characterized by normal or decreased volume of both ventricles associated with atrial enlargement (left or bi-atrial), normal LV wall thickness, normal atrioventricular valve function/structure, impaired ventricular filling with restrictive physiology, and normal (or near normal) systolic function, please see Figure 5 [4, 116].
The clinical course is defined by the inability to fill the ventricles due to poor ventricular relaxation, which limits the cardiac output. The disease may manifest with exercise intolerance, dyspnea, edema, atrial fibrillation, syncope, or sudden cardiac death. The hallmark of non-invasive imaging is atrial or bi-atrial enlargement. Normal or mild concentric hypertrophy with normal or reduced ventricular cavity can also be seen. Familial disease has been reported in 30% of cases and usually exhibits autosomal dominant inheritance. However, autosomal recessive, X-linked, and mitochondrial-transmitted disease have also been reported [117]. Most patients with RCM harbor gene mutations in sarcomere-encoding genes, such as
Gene | Protein | Pattern of Inheritance | Disease Association | OMIM# | Locus |
---|---|---|---|---|---|
BAG3 | Bcl2-Associated Athanogene 3 | AD | LVNC, HCM, DCM | 603883 | 14q24.3 |
DES | Desmin | AD, AR | RCM, DCM, ACM | 125660 | 17q21 |
FLNC | Filamin C | AD | RCM, HCM, ACM, LVNC | 102565 | 10q22.2 |
MYBPC3 | Myosin-Binding Protein C, Cardiac | AD | RCM, HCM, DCM, LVNC | 600958 | Xq28 |
MYH7 | Myosin, Heavy Chain 7, Cardiac Muscle, Beta | AD | RCM, HCM, DCM, LVNC | 160760 | 7p14.2 |
MYL3 | Myosin, Light Chain 3, Alkali, Ventricular, Skeletal, Slow | AD, AR | RCM, HCM | 160790 | 1q32 |
MYOZ2 | Myozenin 2 | AD | RCM, HCM, DCM | 605602 | 3p25.1 |
MYPN | Myopalladin | AD | RCM, HCM, DCM | 608517 | 12q23.1 |
TNNI3 | Troponin I Type 3 (Cardiac) | AD | RCM, HCM, DCM | 191044 | 3p21.1 |
TNNT2 | Troponin T Type 2 (Cardiac) | AD | RCM, HCM, DCM, LVNC | 191045 | 17q12 |
TPM1 | Tropomyosin 1 (Alpha) | AD | RCM, HCM, DCM | 191010 | 19q13.4 |
RCM can be classified based on the underlying process: non-infiltrative; infiltrative; associated with storage diseases; idiopathic; or combined with DCM, HCM, and LVNC [116]. As with DCM, many previous cases deemed idiopathic are later found to harbor causative pathogenic variants in sarcomeric genes. Non-infiltrative causes of RCM include scleroderma and systemic sclerosis with well-described polymorphisms in genes coding for ECM proteins [121]. Pseudoxanthoma elasticum is an inherited disorder associated with accumulation of mineralized elastic fibers that may lead to blindness, coronary arterial occlusive disease, and RCM. The
Lysosomal storage disorders are characterized by abnormal lysosomal metabolism leading to accumulation of various glycosaminoglycans, glycoproteins, or glycolipids within lysosomes of various tissues, including the myocardium. Gaucher disease and Fabry disease (two of the most common lysosomal disorders) may manifest as CM (HCM or RCM), valvular disease, coronary artery disease, and/or aortic enlargement [127].
Mucopolysaccharidoses (Hurler and Hunter diseases) are characterized by the deficiency of enzymes required for the breakdown of glycosaminoglycans. Thus, these diseases are considered lysosomal storage disorders. Cardiac manifestations start from childhood and include RCM, endocardial fibroelastosis, and valvular disease including thickening of the leaflets with resultant stenosis and/or insufficiency. Storage diseases such as hemochromatosis (mutation in the
In summary, CM is a widely variable disease process with a similarly variable pattern of genetic inheritance. Our understanding of the interplay between genetic mutation and disease phenotype is ever-evolving and merits much deeper investigation.
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