Genetics of Cardiomyopathies

Gary S. Beasley

Hugo Martinez

Jeffrey A. Towbin

INTRODUCTION

Primary cardiomyopathies, which include dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), arrhythmogenic cardiomyopathy (ACM), and left ventricular noncompaction cardiomyopathy (LVNC), remain major causes of morbidity and mortality in the world.¹,²,³,⁴ These classified forms of cardiomyopathy have diverse clinical, structural, morphological, and functional presentations. Among the various types of cardiomyopathies, DCM represents the most common form in adults and children, accounting for approximately 40% of all cases in children. This is followed by HCM, LVNC, and, least commonly, ACM and RCM.¹,²,³,⁴

After over three decades of genetic and molecular research, many causative genes have been identified, and overlap in the genetic causes of the various forms of cardiomyopathies have also been identified in which defects in the same gene could lead to allelic disorders.¹,²,³,⁴,⁵,⁶,⁷,⁸ Generally, there are mechanistic “final common pathways” that predominate for each of the forms of cardiomyopathy (Figure 67.1).⁹,¹⁰ For instance, DCM is typically caused by variants in genes encoding structural proteins such as cytoskeletal and sarcomeric proteins and, in this case, usually presents with features of heart failure.¹⁰ HCM is considered a disease of the sarcomere and usually presents with syncope or sudden death and may develop features of heart failure with preserved ejection fraction (HFpEF).¹¹,¹²,¹³ Arrhythmias, which are most commonly caused by pathogenic variants in genes encoding ion channels when isolated, may also be a late manifestation in DCM or other forms of cardiomyopathy.¹⁴ This chapter will present the different forms of cardiomyopathy and what is currently known about the genetic basis and the pathophysiological mechanisms responsible for the disorders.

FIGURE 67.1 Primary pathways responsible for the different cardiomyopathy and arrhythmia phenotypes. The cascade pathways include interacting proteins, medications, mitochondrial disturbance, or other modifying factors. ACM, arrhythmogenic cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVNC, left ventricular noncompaction; RCM, restrictive cardiomyopathy.

DILATED CARDIOMYOPATHY

Dilated cardiomyopathy (DCM) is characterized by an enlarged left ventricular chamber, left ventricular wall thinning, and systolic dysfunction in the absence of abnormal loading conditions (ie, hypertension and valvular disease) or coronary artery disease sufficient to cause global systolic impairment (Figure 67.2A).¹,²,³,⁴,⁵,¹⁵ Individuals with DCM commonly present with symptomatic heart failure, arrhythmias, or conduction disturbance.¹,²,³,⁴ DCM in children has an estimated incidence of approximately 0.57 per 100,000 cases compared with the report of 1/2500 incidence in adult subjects.¹⁶ However, the actual incidences could be far higher because of the reduced
detection rate caused by incomplete penetrance and variable expressivity observed in DCM, which can lead to a prolonged asymptomatic period preceding the development of overt heart failure.¹,²,³,⁴,¹⁶ A disease prevalence of 1:250 to 500 for DCM has been reported in adults.¹⁷

FIGURE 67.2 The different forms of classified cardiomyopathies. Causative genes for restrictive cardiomyopathy (RCM) and arrhythmogenic cardiomyopathy (ACM). A. Dilated cardiomyopathy with dilated left ventricle and depressed systolic function. B. Hypertrophic cardiomyopathy with severe hypertrophy, small ventricular chambers, and mildly dilated left atrium. Systolic function is hypercontractile, and there is diastolic dysfunction. C. Restrictive cardiomyopathy with dilated atria, normal ventricular size and systolic function, and diastolic dysfunction. D. Left ventricular noncompaction cardiomyopathy. Note the heavy trabeculations in the left ventricular apex and posterior wall. E. Cardiac magnetic resonance imaging of arrhythmogenic right ventricular cardiomyopathy. Note the markedly dilated right ventricle.

Although a proportion of DCM could be attributed to infections causing myocarditis, with reports estimating 16% to 34% of DCM cases in childhood and 12% to 17% in adults in North America,¹,²,⁸,¹⁶,¹⁸,¹⁹,²⁰ a large fraction of DCM is genetic in origin. These may be either sporadic, if there is no previous family history and screening of first-degree relatives is negative, or familial, if it occurs in two or more close relatives.¹,²,³,⁴,¹⁶ Although familial DCM is reported in approximately 20% to 35% of adult cases,¹⁵,²¹,²² it is estimated to occur in up to 67% of cases after accurate screening of the relatives of idiopathic DCM subjects.⁸ Most cases are inherited as autosomal dominant, X-linked, or autosomal recessive traits, and, less frequently, as mitochondrial inheritance.²³,²⁴,²⁵,²⁶ In approximately 30% of familial cases, a genetic cause can be identified.

DCM is caused by disturbances in “final common pathways” that result in disturbance of force transmission and can include sarcomere, Z-disk, and cytoskeleton proteins that are affected by relevant gene mutations.⁶,⁸,⁹,¹⁰ Genes encoding proteins of the ion channels, the nuclear envelope, mitochondrial proteins, transcription factors, and heat shock chaperones are alternative sites of gene mutation²⁷ (Table 67.1). Although more than 100 genes are implicated as mutation targets in familial DCM, very few of them have been shown to account for greater than or equal 5% of this disease.²⁸ Most of the genes with pathogenic mutations are missense mutations (different amino acids in a protein sequence), but nonsense, frameshift, deletion, and other forms of mutations may occur. “Private” or unique to a family and very rare mutations are the standard finding in DCM.²⁹,³⁰

In DCM, pathogenic gene variants that affect critical pathways of contractile function, ion distribution, or cellular function have the potential to result in a DCM phenotype. This was initially demonstrated by the identification of the dystrophin (DMD) gene, the gene responsible for Duchenne and Becker muscular dystrophy and causative of the associated skeletal myopathy and DCM. The DMD gene was subsequently identified as the gene responsible for the X-linked form of DCM as well.³¹,³² However, defects in the DMD gene could explain only a fraction of all DCM cases; later, other genes responsible for DCM were identified, defining DCM as a genetically heterogeneous entity. Based on these findings, we formulated the “final common pathway” hypothesis (1998) in which it was suggested that abnormalities in other genes encoding for dystrophin-associated proteins and proteins involved in the structural formation and maintenance of cardiomyocyte structure and contractile function could also potentially lead to the development of DCM.⁹,¹⁰ It is now known that

perturbation of cardiomyocyte proteins involved in contractile force generation and transmission (eg, cytoskeletal, sarcomeric, and ion channel proteins) are involved in the pathogenesis of DCM.⁶,⁷,⁸,¹¹,¹²,¹³,¹⁴,¹⁷,²⁷,³³ In vitro models and animal models recapitulating the human disease suggest that alteration of the protein continuum connecting the cardiomyocyte plasma membrane (sarcolemma) to the sarcomere, and through the intermediate filaments, to the perinuclear membrane, can lead to a transient hypertrophic phase, followed by decompensated systolic performance, left ventricular wall thinning, and left ventricular chamber dilation.³⁴,³⁵,³⁶

TABLE 67.1 Genes Associated With Cardiomyopathies and Their Allelic Disorders

Gene	OMIM^a	Locus	Gene Name^b	Associated Phenotypes^b
ABCC9	601439	12p12.1	ATP-binding cassette, sub-family C (CFTR/MRP), member 9	DCM
ACTC1	102540	15q14	Actin, α, cardiac muscle 1	DCM HCM RCM
ACTN2	102573	1q42-q43	Actinin, α 2	DCM HCM
BAG3	603883	10q25.2-q26.2	BCL2-associated athanogene 3	MFM DCM
CSRP3	600824	11p15.1	Cysteine and glycine-rich protein 3 (cardiac LIM protein)	DCM LVNC HCM
DES	125660	2q35	Desmin	MFM DCM RCM
DMD	300377	Xp21.2	Dystrophin	DMD BMD DCM
DSC2	125645	18q12.1	Desmocollin 2	ARVC
DSG2	125671	18q12.1	Desmoglein 2	ARVC ALVC DCM
DSP	125647	6p24	Desmoplakin	ARVC ALVC DCM
DTNA	601239	18q12.1	Dystrobrevin, α	LVNC
EMD	300384	Xq28	Emerin	EDMD DCM
EYA4	603550	6q23-q24	Eyes absent homolog 4 (Drosophila)	DFNA DCM
FKTN	607440	9q31	Fukutin	FCMD DCM
HCN4	605206	15q24.1	Hyperpolarization activated cyclic nucleotide-gated potassium channel 4	LVNC CD MVP
HSPB7	610692	1p36.13	Heat shock 27kDa protein family, member 7	DCM
JUP	173325	17q21	Junctional plakoglobin	ARVC ND
LAMP2	309060	Xq24	Lysosomal-associated membrane protein 2	DD HCM DCM
LDB3	605906	10q22-q23	LIM-domain binding 3	DCM ± LVNC MFM
LMNA	150330	1q21.2	Lamin A/C	DCM ± CD CMT2B1 EDMD HGPS LGMD MADA FPLD2
MYBPC3	600958	11p11.2	Myosin-binding protein C, cardiac	DCM HCM
MYH6	160710	14q12	Myosin, heavy chain 6, cardiac muscle, α	DCM HCM
MYH7	160760	14q12	Myosin, heavy chain 7, cardiac muscle, β	DCM HCM RCM LVNC
MYL2	160781	12q23-q24	Myosin, light chain 2, regulatory, cardiac, slow	HCM
MYL3	160790	3p21.3-21.2	Myosin, light chain 3, alkali light chain; ventricular isoform, skeletal isoform, slow	HCM
MYPN	608517	10q21.1	Myopalladin	DCM RCM HCM
NEBL	605491	10p13-p12	Nebulette	DCM
NEXN	613121	1p31.1	Nexilin (F actin binding protein)	DCM HCM
PKP2	602861	12p11	Plakophilin 2	ARVC
PKP4	604276	2q23-q31	Plakophilin 4	ARVC
PLN	172405	6q22.1	Phospholamban	DCM
PRKAG2	602743	7q36.1	Protein kinase, AMP-activated, γ 2 noncatalytic subunit	HCM ± WPW FCNCG
PSEN1	104311	14q24.3	Presenilin 1	AD DCM FAI
PSEN2	600759	1q31-q42	Presenilin 2 (Alzheimer disease 4)	AD-4 DCM
RBM20	613171	10q25.2	RNA binding motif protein 20	DCM
RYR2	180902	1q43	Ryanodine receptor 2 (cardiac)	ARVC CPVT1
SCN5A	600163	3p21	Sodium channel, voltage-gated, type V, α subunit	BRS LQTS DCM ± CD
SGCB	600900	13q12	Sarcoglycan, β	LGMD2E DCM
SGCD	601411	5q33-q34	Sarcoglycan, delta	LGMD2F DCM
TAZ	300394	Xq28	Tafazzin	BTS LVNC DCM
TCAP	604488	17q12	Titin-cap (telethonin)	LGMD2G HCM DCM
TGFB3	190230	14q24	Transforming growth factor, β 3	ARVC
TMEM43	612048	3p25.1	Transmembrane protein 43	ARVC
TMPO	188380	12q22	Thymopoietin	DCM
TNNC1	191040	3p21.1	Troponin C type 1 (slow)	DCM HCM
TNNI3	191044	19q13.4	Troponin I type 3 (cardiac)	DCM HCM RCM
TNNT2	191045	1q32	Troponin T type 2 (cardiac)	DCM HCM RCM
TPM1	191010	15q22.1	Tropomyosin 1 (α)	DCM HCM
TTN	188840	2q31	Titin	TMD LGMD2J EOMFC DCM HCM HMERF
VCL	193065	10q22.1-q23	Vinculin	DCM HCM
^aOMIM, online Mendelian inheritance in man (www.ncbi.nlm.nih.gov/omim) ^bGenetic Home References (ghr.nlm.nih.gov/)
AD, Alzheimer disease; ARVC, arrhythmogenic right ventricular cardiomyopathy; ATP, adenosine triphosphate; BCL-2, B-cell lymphoma 2; BMD, Becker muscular dystrophy; BRS, Brugada syndrome; CD, conduction defects; CFTR, cystic fibrosis transmembrane conductance regulator; CMT2B1, Charcot-Marie-Tooth disease type 2B1; CPVT, catecholaminergic polymorphic ventricular tachycardia; DCM, dilated cardiomyopathy; DD, Danon disease; DFNA, autosomal dominant late-onset progressive nonsyndromic deafness; DMD, Duchenne muscular dystrophy; EDMD, Emery-Dreifuss muscular dystrophy; EOMFC, early-onset myopathy with fatal cardiomyopathy; FAI, familial acne inverse; FCMD, Fukuyama congenital muscular dystrophy; FCNCG, fatal congenital nonlysosomal cardiac glycogenosis; FPLD2, familial partial lipodystrophy of the Dunnigan type; HCM, hypertrophic cardiomyopathy; HGPS, Hutchinson-Gilford progeria syndrome; HMERF, myopathy with early respiratory muscle involvement; LGMD, limb-girdle muscular dystrophy; LQTS, long-QT syndrome; LVNC, left ventricular noncompaction; MADA, mandibuloacral dysplasia type A with partial lipodystrophy; MFM, myofibrillar myopathy; MRP, multidrug resistance-associated protein; MVP, mitral valve prolapse; ND, Naxos disease; nNOS, neuronal nitric oxide synthase; RCM, restrictive cardiomyopathy; TMD, tibial muscular dystrophy, tardive; VCFS, velocardiofacial syndrome; WPW, Wolff-Parkinson-White syndrome.

Additionally, more than 30 genes identified to cause DCM in isolation, genes have also been identified that are associated with syndromic forms of DCM, such as genes involved in metabolism and mitochondrial function, besides loci allelic to other cardiomyopathic phenotypes.³⁷ In particular, primary diseases of the skeletal muscle, such as various forms of muscular dystrophy and other skeletal myopathies, frequently present with a DCM phenotype.³⁸,³⁹,⁴⁰,⁴¹

Despite the large number of genes associated with DCM, they account for only approximately 40% of all cases. Horvat et al performed genetic screening in 532 DCM patients and 527 healthy control subjects.⁴² Variants that were protein-altering (truncating, missense) and rare (defined here by minor allele frequency less than 0.1% in the European subgroup in the Exome Sequencing Project database) in a set of 41 cardiomyopathy-associated genes were evaluated. Variants that met these criteria were found in 407 (77%) DCM cases and in 348 (66%) control subjects (P = .0002), with the number of rare variants per person ranging from 0 to 13 (mean 1.63) in DCM cases and from 0 to 8 (mean 1.24) in controls (P < .0001). With notable exceptions—such as titin (TTN), lamin A/C (LMNA), β-myosin heavy chain 7 (MYH7), and RNA binding motif protein 20 (RBM20)—relatively few genes carried a statistically significant excess burden of rare variants in DCM versus control cases.⁴² Indeed, from a comprehensive search of publications that included family studies, in vitro data, and animal models, we found that only 14 of 41 genes (34%) represented on two genetic testing panels had robust genetic and functional evidence for roles in DCM causation.⁴² Interestingly, this refined set of 14 genes encoded a range of cardiomyocyte components and did not alter the prevailing hypothesis that familial DCM has heterogeneous molecular origins.⁴²

In addition, genes encoding for ion channels, such as the cardiac sodium channel (SCN5A), which causes long-QT syndrome (LQTS) and Brugada syndrome, is also implicated in the pathogenesis of DCM and, in particular, mutations
in SCN5A that affect the S4-voltage sensor are seen in subjects with DCM and arrhythmias.¹⁴,⁴³,⁴⁴,⁴⁵,⁴⁶ This suggests that ion channels not only influence the electrocardiographic (ECG) findings and potentiate arrhythmias in DCM¹⁴ but may also weaken the cardiomyocytes structure leading to DCM and vice versa, as demonstrated in a mouse model harboring the LDB3-encoded ZASP (Z-band alternatively spliced PDZ-motif) mutation causing DCM in humans.⁴⁷ Another potential mechanism, particularly in the case of SCN5A, is its relationship with dystrophin. SCN5A binds to dystrophin and could potentially disrupt the function of dystrophin and lead to a dystrophin-related cardiomyopathy, as would be predicted by the “final common pathway” hypothesis.⁹,¹⁰

Clinically, the presentation of idiopathic, acquired, and genetic forms of DCM is indistinguishable. This suggests that clinical evaluation of relatives of children with DCM should always be considered when a diagnosis of DCM is reached. Unfortunately, a significant proportion of DCM remains idiopathic, where a firm etiologic diagnosis cannot be reached. This suggests that more genes are yet to be discovered and that modifiers likely play a significant role in disease development.

HYPERTROPHIC CARDIOMYOPATHY

Hypertrophic cardiomyopathy (HCM) is one of the most common genetic disorders with a prevalence of 1/500, representing one of the most frequent causes of sudden cardiac death in young athletes in the United States.⁴⁸,⁴⁹ HCM is characterized by excessive thickening generally limited to the left ventricular myocardium and interventricular septum, in the absence of conditions that increase afterload such as aortic stenosis or systemic hypertension, and morphologically is typically characterized by myocyte disarray (Figure 67.2B).³,⁴,⁸,⁴⁹ The interventricular septal thickening most commonly demonstrates asymmetric hypertrophy but focal areas of septal hypertrophy or concentric hypertrophy may occur. Left ventricular outflow tract obstruction may also occur. Individuals with HCM may be asymptomatic or present with or develop signs of heart failure or sudden death.⁴⁸,⁴⁹ Clinical presentations therefore include syncope or nonresuscitated sudden death, dyspnea, diaphoresis, chest pain, palpitations, or arrhythmias. The age of onset of HCM-related symptoms varies from infancy to adulthood. However, most appear in adolescence.⁴⁹

As previously described for DCM, primary HCM has a genetic basis in most cases. Many genes, with many encoding for sarcomeric proteins¹¹ that are mainly involved in force generation, have been identified to cause HCM, and many of them are allelic to DCM and other cardiomyopathies (Table 67.1).⁵⁰

Similar to DCM, HCM is characterized by significant genetic and allelic heterogeneity and variable expressivity.¹¹,¹²,¹³ However, contrary to DCM, genetic testing in HCM using the current technology has a high-detection rate because mutations in four sarcomeric genes, β-myosin heavy chain (MYH7), myosin-binding protein C (MYBPC3), cardiac troponin T (TNNT2), and cardiac troponin I (TNNI3), appear to cause approximately 80% of all familial HCM cases. Mutations can also be identified in about 40% of sporadic and idiopathic cases of HCM.¹¹ Although genotype-phenotype correlation is imperfect, it has been reported that mutations in MYH7 are associated with early-onset disease, and in some cases, a more severe phenotype, while MYBPC3 mutations have been identified in subjects with later onset presentation, and TNNT2 mutations are associated with a high incidence of sudden cardiac death.¹¹,⁵¹ That said, both MYH7 and MYBPC3 mutations have been identified in children as young as less than 1 year of age.⁵²,⁵³,⁵⁴

HCM is a monogenic disorder in most cases, although double heterozygote mutations have been described and may be associated with earlier-onset and a more dramatic phenotype.¹¹,⁵⁵

Despite the high-detection rate of clinical genetic testing in HCM, the lack of good genotype-phenotype correlation has lessened the clinical utility of genetic screening in affected patients, although this is improving. Lopes et al demonstrated that the presence of any sarcomere variant is associated with an asymmetric septal hypertrophy pattern, younger age at presentation, family history of HCM and sudden cardiac death, and female gender.⁵⁶ This study also showed that patients with pathogenic variants in sarcomeric genes and proteins had higher cardiovascular and sudden death-related mortality during follow-up. Patients with more than one pathogenic sarcomere variant had more sudden cardiac death risk markers, consistent with previously published suggestions of a gene dose effect.¹³,²⁶,²⁷,²⁸,⁵⁷,⁵⁸ A low number of outcome events occurred during follow-up, and this may have biased the survival analysis and precluded an analysis of other associations, including the effect of carrying multiple compared with single variants. More recently, Robyns and colleagues, using the stringent American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) criteria, identified a mutation in 37% of patients studied with the majority of them in MYBPC3, MYH7, and the troponin complex.⁵⁹ The genetic yield was very similar to what was previously published in a large cohort of almost 3000 unselected index patients.⁵⁹ Patients with a mutation were younger at diagnosis and had more severe disease including more pronounced hypertrophy and more frequent syncope. However, the sudden cardiac death rate was very similar. MYBPC3 mutation carriers had a worse outcome compared with troponin complex mutations and a trend toward worse outcome compared to MYH7 mutation carriers and mutation-negative patients. This contrasts with earlier reports claiming worse survival in MYH7 mutation carriers compared with MYBPC3.⁶⁰,⁶¹ In addition, the presence of negative T waves in the lateral ECG leads was a negative predictor of carrying a mutation.

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