**1. Introduction**

Heart failure afflicts about 26 million patients worldwide. The estimated economic burden related to heart failure is 120 billion US dollars [1]. Dilated cardiomyopathy (DCM), referred to a group of heart muscle disorders characterized by heart chamber dilation and systolic dysfunction, is a common cause of heart failure. DCM is the most common form of non-ischemic cardiomyopathy and the most common indication in patients who need heart transplantation [2, 3]. In the pediatric, nearly 50% of patients dying suddenly or undergoing cardiac transplantation are affected by cardiomyopathy, predominantly by DCM [4]. In the young, DCM is the most frequent cause of heart failure [5]. In the adult, it is the second most common cause of heart failure (after the coronary heart disease), underlying about one third of all heart failure cases [1]. While the true prevalence for DCM in general population is not fully defined yet due to lack of well-designed large-scale population based studies, its estimated prevalence ranges from 1 in 2500 to 1 in 250 people [6]. The annual incidence of DCM

is approximately 7 cases per 10,000 individuals, and males are about 3 times more frequently affected than females [2, 7, 8].

Classically, DCM is defined based on two major criteria: 1) left LV fractional shortening <25% (> 2 standard deviations [SD]) and/or LV ejection fraction <45% (>2 SD); and 2) LV end-diastolic diameter greater than 117% of the predicated value corrected for age and body surface area. DCM is diagnosed when any other known cause of myocardial diseases are excluded [9]. The updated definitions of DCM are left ventricular or biventricular systolic dysfunction and dilatation that are not explained by abnormal loading conditions or coronary artery disease [10].

DCM is caused by a variety of etiologies, including acquired, genetic and/or mixed origins. Acquired risk factors such as infection, myocarditis, drug toxin, autoimmune response, excess alcohol consumption and metabolic disorders are recognized to cause DCM. Primary DCM results when all these acquired factors are exclude, which can be either idiopathic or familial. Familial DCM (FDC) is classified when two or more family members are diagnosed in first-degree relatives. The prevalence of familial DCM differs in different patient cohorts, estimated to range from 20–50% of all DCM cases. The remaining DCM cases are thus classified as idiopathic [6, 11]. However, the frequency of familial DCM is believed to be underestimated, due to the limitation of large pedigree and family's availability for diagnostic screening. Genetic factors which predispose to DCM have been increasingly recognized. Since the discovery of the first disease causative gene to cardiomyopathy [12], to date, more than 50 genes have been identified to associate with DCM and the number is still increasing. Genetic mutations in all these genes combined can explain about 40–50% of familial DCM cases, underpinning the genetic determinant of this disease [6]. The familial DCM appears to be inherited as a monogenic trait and is mainly transmitted in an autosomal dominant inheritance pattern, manifesting incomplete, age-related penetrance and variable expression. Other patterns such as autosomal recessive, X-linked and mitochondrial inheritance also occurs in a small portion of the familial DCM cases [6, 13].

Current management of DCM is mainly focused on treating patients with symptoms following the standard guidelines, similar to treating other forms of heart failure with reduced ejection fraction (EF). The guideline driven therapies mostly adapt a "one-size-fits-all" approach that uses β-adrenergic blockers, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers to improve cardiac function and symptom by reducing congestion and management of arrhythmia [14, 15]. Recently, several new additions of armamentarium are also implemented in the treatment options [16–18]. Despite of advances in these treatment protocols, DCM remains one of the major reasons for patients needed for heart transplantation, and the morbidity and mortality rate of DCM still remains unacceptably high. Thus, the current management of DCM with the "onesize-fits-all" strategy is challenged. More novel and effective and individualized treatment options are desirable.

Considering the genetic determinant of DCM, and up to 50% of familial DCM patients have a genetic origin, genotype-targeted therapies, by directly targeting at the specific gene mutations, have emerged as promising strategies toward development of more effective and individualized treatment. In this chapter, we firstly review definitive genes linked to DCM and classify them based on their intracellular localization (**Figure 1**), with a major focus on genes most commonly implicated in DCM, and highlight their underlying pathophysiological mechanism of action if known (**Table 1**). Next, we discuss progress and challenges on the emerging genotype-based therapeutic strategies for effective and individualized medicine explored in the treatment of DCM (**Table 2**), which hold the opportunities to ultimately improve patient outcome in the future.

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**Sarcomere**

**Figure 1.**

*ACTC1* Alpha cardiac actin

*implicated in dilated cardiomyopathy disease.*

*MYH7* Beta-myosin

*TNNC1* Cardiac

*TNNT2* Cardiac

**Cytoskeleton**

**Nuclear envelope**

*TPM1* Tropomyosin

heavy chain

troponin C

troponin T

alpha-1 chain

*TNNI3* Cardiac troponin I Cardiac muscle

*DES* Desmin Contractile force

*DMD* Dystrophin Contractile force

*SGCD* δ-sarcoglycan Structural component

*EMD* Emerin Nuclear membrane

*Genetic Determinant of Familial Dilated Cardiomyopathy and Genotype-Targeted Therapeutic…*

**Gene Protein Function Frequency and** 

Structural component of thin filament

*Subcellular localization of the protein encoded by dilated cardiomyopathy disease genes. The graphic shows schematic representations and approximate intracellular localization of the encoded proteins by genes strongly* 

> Cardiac muscle contraction

> Cardiac muscle contraction

contraction

Cardiac muscle contraction

Cardiac muscle contraction

transduction

transduction

of dystrophinglycoprotein complex

anchorage

*TTN* Titin Sarcomere scaffold 15–25% of DCM; HCM Autosomal

**overlapping phenotype**

<1% of DCM; HCM,

5% of DCM; HCM, ACM, LVNV

<1% of DCM; HCM,

3% of DCM; HCM, ACM, LVNC

1–2% of DCM; HCM,

<1% of DCM; HCM Autosomal

LVNC

LVNC

LVNC

<1% of DCM; Desminopathies

<1% of DCM; Duchenne/Becker muscular dystrophy

LGMD2E

<1% of DCM; HCM,

<1% of DCM; EMDM X-linked

**Inheritance pattern**

Autosomal dominant

Autosomal dominant

Autosomal dominant

recessive

Autosomal dominant

Autosomal dominant

dominant

Autosomal dominant

X-linked

Autosomal recessive

*DOI: http://dx.doi.org/10.5772/intechopen.94434*

*Genetic Determinant of Familial Dilated Cardiomyopathy and Genotype-Targeted Therapeutic… DOI: http://dx.doi.org/10.5772/intechopen.94434*

#### **Figure 1.**

*Cardiac Diseases - Novel Aspects of Cardiac Risk, Cardiorenal Pathology and Cardiac Interventions*

is approximately 7 cases per 10,000 individuals, and males are about 3 times more

also occurs in a small portion of the familial DCM cases [6, 13].

Current management of DCM is mainly focused on treating patients with symptoms following the standard guidelines, similar to treating other forms of heart failure with reduced ejection fraction (EF). The guideline driven therapies mostly adapt a "one-size-fits-all" approach that uses β-adrenergic blockers, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers to improve cardiac function and symptom by reducing congestion and management of arrhythmia [14, 15]. Recently, several new additions of armamentarium are also implemented in the treatment options [16–18]. Despite of advances in these treatment protocols, DCM remains one of the major reasons for patients needed for heart transplantation, and the morbidity and mortality rate of DCM still remains unacceptably high. Thus, the current management of DCM with the "onesize-fits-all" strategy is challenged. More novel and effective and individualized

Considering the genetic determinant of DCM, and up to 50% of familial DCM patients have a genetic origin, genotype-targeted therapies, by directly targeting at the specific gene mutations, have emerged as promising strategies toward development of more effective and individualized treatment. In this chapter, we firstly review definitive genes linked to DCM and classify them based on their intracellular localization (**Figure 1**), with a major focus on genes most commonly implicated in DCM, and highlight their underlying pathophysiological mechanism of action if known (**Table 1**). Next, we discuss progress and challenges on the emerging genotype-based therapeutic strategies for effective and individualized medicine explored in the treatment of DCM (**Table 2**), which hold the opportunities to

Classically, DCM is defined based on two major criteria: 1) left LV fractional shortening <25% (> 2 standard deviations [SD]) and/or LV ejection fraction <45% (>2 SD); and 2) LV end-diastolic diameter greater than 117% of the predicated value corrected for age and body surface area. DCM is diagnosed when any other known cause of myocardial diseases are excluded [9]. The updated definitions of DCM are left ventricular or biventricular systolic dysfunction and dilatation that are not explained by abnormal loading conditions or coronary artery disease [10]. DCM is caused by a variety of etiologies, including acquired, genetic and/or mixed origins. Acquired risk factors such as infection, myocarditis, drug toxin, autoimmune response, excess alcohol consumption and metabolic disorders are recognized to cause DCM. Primary DCM results when all these acquired factors are exclude, which can be either idiopathic or familial. Familial DCM (FDC) is classified when two or more family members are diagnosed in first-degree relatives. The prevalence of familial DCM differs in different patient cohorts, estimated to range from 20–50% of all DCM cases. The remaining DCM cases are thus classified as idiopathic [6, 11]. However, the frequency of familial DCM is believed to be underestimated, due to the limitation of large pedigree and family's availability for diagnostic screening. Genetic factors which predispose to DCM have been increasingly recognized. Since the discovery of the first disease causative gene to cardiomyopathy [12], to date, more than 50 genes have been identified to associate with DCM and the number is still increasing. Genetic mutations in all these genes combined can explain about 40–50% of familial DCM cases, underpinning the genetic determinant of this disease [6]. The familial DCM appears to be inherited as a monogenic trait and is mainly transmitted in an autosomal dominant inheritance pattern, manifesting incomplete, age-related penetrance and variable expression. Other patterns such as autosomal recessive, X-linked and mitochondrial inheritance

frequently affected than females [2, 7, 8].

**102**

treatment options are desirable.

ultimately improve patient outcome in the future.

*Subcellular localization of the protein encoded by dilated cardiomyopathy disease genes. The graphic shows schematic representations and approximate intracellular localization of the encoded proteins by genes strongly implicated in dilated cardiomyopathy disease.*



*ACM, Arrhythmogenic cardiomyopathy; DCM, dilated cardiomyopathy; EDMD, Emery–Dreifuss muscular dystrophy; LVNC, left ventricular noncompaction; HCM, hypertrophic cardiomyopathy; LGMD, limb-girdle muscular dystrophy; LQTs, long QT syndrome; RCM, restrictive cardiomyopathy.*

#### **Table 1.**

*Genes linked to dilated cardiomyopathy with strong evidence.*


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*Genetic Determinant of Familial Dilated Cardiomyopathy and Genotype-Targeted Therapeutic…*

**Molecular pathophysiology**

Titin protein haploinsufficiency, sarcomere insufficiency, metabolic and energetic adaption, increased sensitivity to mechanical stress

Abnormal PLN protein subcellular localization, calcium handling defects, electrical instability

protein deficiency, sarcolomma instability, increased myocyte apoptosis, reduced expression of miRNA-669a

**Genotype-based therapy**

TALEN genome editing

1) Gene replacement; 2) microRNA overexpression

Exon-skipping [82]

**Reference**

[22, 84]

[83, 88, 89]

Extensive studies on genetic basis of DCM underscored profound heterogeneous nature of DCM disease. DCM variants mutate genes encoding a broad spectrum of proteins with distinct functions and intracellular localization have been identified (**Figure 1** and **Table 1**). For example, mutations in genes encoding sarcomere protein involving in mechanosensing and force transmission, encoding nuclear envelope proteins required for the protection of biochemical forces, encoding desmosomal proteins required for maintaining the structural integrity of desomosome, encoding ion channels and molecules involving in calcium handling, encoding chaperone proteins, transcription factors and RNA-binding proteins have all been identified to cause DCM. Specific variants in these genes may alter various signaling pathways and cellular structures in cardiomyocyte that can disrupt the mechanism of cardiac muscle contraction and function, leading to

Sarcomere is the basic contractile unit mainly composed of thin and thick filaments. Mutations in sarcomere genes are one of the most important causes of DCM, which have been identified in about one third of DCM [19–21]. In addition to cause DCM, mutations in sarcomere genes often lead to overlapping phenotypes of hypertrophic cardiomyopathy (HCM), another major genetic type of cardiomyopathy characterized by ventricular wall thickness and diastolic dysfunction. Genes with definitive evidence, supported by studies from multiple centers/groups, with both

*DOI: http://dx.doi.org/10.5772/intechopen.94434*

*TTN* Truncating DCM, HCM,

**Clinical phenotype**

ventricular arrhythmias

Ventricular dilation, contractile dysfunction and ventricular arrhythmias, heart failure by middle age

*SGCD* Deletion DCM, HCM δ-sarcoglycan

**Gene Variant type**

*PLN* Missense

**Table 2.**

Deletion

**2. Genetic causes of familial DCM**

*Examples of gene-targeted therapeutic strategies.*

common phenotypes of DCM.

**2.1 Sarcomere genes**


*Genetic Determinant of Familial Dilated Cardiomyopathy and Genotype-Targeted Therapeutic… DOI: http://dx.doi.org/10.5772/intechopen.94434*

**Table 2.**

*Cardiac Diseases - Novel Aspects of Cardiac Risk, Cardiorenal Pathology and Cardiac Interventions*

**overlapping phenotype**

2% of DCM Autosomal

2% of DCM; ACM Autosomal

6% of DCM; EMDM,

2–3% of DCM; LQTs Brugada syndrome

3% of DCM; Myofibrillar

<1% of DCM; HCM,

3-Methylglutaconic aciduria, type V

<1% of DCM; HCM, Barth syndrome

<1% of DCM; HCM,

**Genotype-based therapy**

1) Exon skipping; 2) Mini dystrophin gene replacement; 3) CRISPRA/Cas9 genome editing; 4) Stop codon readthrough

1) Preventive therapy, lower the threshold for cardiac defibrillator implantation; 2) p38 inhibition; 3) Transsplicing; 4) Stop codon readthrough

ACM

LGMD1B

myopathy

RCM

Protein transporter <1% of DCM;

**Inheritance pattern**

Autosomal dominant

dominant

Autosomal dominant

Autosomal dominant

Autosomal dominant

recessive

Autosomal recessive

X-linked

Autosomal dominant

**Reference**

[60–62, 67, 71–73, 80]

[29, 30, 58, 75, 79]

**Gene Protein Function Frequency and** 

structure

Regulator of cardiac gene splicing

Sodium channel protein

Co-chaperone, inhibition of apoptosis

crosslinking

component of desomosome, cell–cell mechanotransmission

transacylase

pump

*muscular dystrophy; LQTs, long QT syndrome; RCM, restrictive cardiomyopathy.*

**Clinical phenotype**

DCM with high penetrance, high risk of arrhythmia, early lethality

DCM, DMD, Becker muscular dystrophy, premature death

Regulator of calcium

*ACM, Arrhythmogenic cardiomyopathy; DCM, dilated cardiomyopathy; EDMD, Emery–Dreifuss muscular dystrophy; LVNC, left ventricular noncompaction; HCM, hypertrophic cardiomyopathy; LGMD, limb-girdle* 

> **Molecular pathophysiology**

Absence of functional dystrophin protein, replacement of muscle by fibrotic and adipose tissue, contraction weakness

Lamins A and C proteins haploinsufficiency,

nuclear malformations, biomechanical defects, activation of p38 kinase pathway

*LMNA* Lamin A/C Nuclear envelope

**Nucleus**

**Ion channel**

**Z-disk**

**Desomosome**

**Mitochondrion**

*RBM20* RNA-binding

*SCN5A* Sodium voltage-

*BAG3* BCL2-associated

*DNAJC19* DnaJ heat shock

**Sarcoplasmic reticulum** *PLN* Cardiac

**Gene Variant type**

*DMD* Nonsense

*LMNA* Nonsense

Deletion

Deletion

protein 20

gated channel alpha subunit 5

athanogene 3

*FLNC* Flamin-C Actin filament

*DSP* Desmoplakin Structural

protein family homolog, C19

phospholamba

*TAZ* Tafazzin Phospholipid

*Genes linked to dilated cardiomyopathy with strong evidence.*

**104**

**Table 1.**

*Examples of gene-targeted therapeutic strategies.*
