**3. Dilated cardiomyopathy**

Dilated cardiomyopathy is the most common cause of congestive heart failure in young patients. The prevalence is ~36: 100,000 in the U.S. It is characterized by ventricular chamber enlargement, thin wall thickness, impaired left ventricular systolic function, and there is also, in some cases, secondary diastolic dysfunction. The most common feature is congestive heart failure, though, conduction impairment, syncope and sudden death may also occur. It is an important cause of cardiac transplantation (Sugrue, 1992).

The histological findings are nonspecific and they include myocyte loss and interstitial fibrosis. Familial cases of DCM were initially considered to be quite rare. However, careful screenings have shown that up to 35% of the probands´ relatives have a DCM familial disorder.

different forms of dilated cardiomyopathy. Therefore, autosomal dominant, autosomal recessive, and X-linked inheritance can be observed. (See Table 2) However, the autosomal dominant pattern is the most frequent mode of inheritance. It has been demonstrated that DCM has reduced penetrance. The age of onset shows great variability though it is usually appears in adulthood (Mangin, 1999). When the mutation is in one of the sarcomeric genes the affected

**HCM gene Symbol Locus name Chromosome locus Protein**

Myosin-binding protein C

Essential myosin light chain

Alpha-myosin heavy chain

Muscle LIM protein

**Table 1.** Sarcomeric genes that cause HCM

Beta-myosin heavy chain *MYH7* CMH1 14q2 Myosin heavy chain,

Troponin T *TNNT2* CMH2 1q32 TroponinT, cardiac muscle

Troponin I *TNNI3* CMH7 19q13.4 TroponinI, cardiac muscle

Alpha-tropomyosin *TPM1* CMH3 15q22.1 Tropomyosin1 alpha chain

Regulatory myosin light chain *MYL2* CMH10 12q24.3 Myosin regulatory light

Actin *ACTC1* CMH11 15q14 Actin, alpha cardiac

Titin *TTN* CMH9 2q24.3 2 Titin

Telethonin *TCAP* CMH11 17q12 1 Telethonin

Cardiac troponin C *TNNC1* CMH13 3p21.1 Troponin C, slow skeletal

cardiac muscle beta

The Role of Genetics in Cardiomyopathy http://dx.doi.org/10.5772/55775 109

chain 2, ventricular/ cardiac muscle isoform

and cardiac muscles

cardiac muscle alpha

protein 3, muscle LIM

muscle 1

isoform

protein

isoform

cardiac-type

*MYBPC3* CMH4 11p11.2 Myosin-binding protein C,

*MYL3* CMH8 3p21 5 Myosin light polypeptide 3

*MYH6* CMH14 14q12 Myosin heavy chain,

*CSRP3* CMH12 11p15. Cysteine and glycine-rich

patients are usually young adults (Aernout Somsen, 2012).

In these families, the pattern of inheritance is variable, so the patients present both locus heterogeneity and allellic heterogeneity. Mutations in many genes have been reported to cause


**Table 1.** Sarcomeric genes that cause HCM

**2. Hypertrophic cardiomyopathy**

cardiovascular disorder (Maron, 2002).

in young athletes while practicing sports.

hypertrophy (Richard, 2006, Ho, 2007).

(Richard, 2006 Hayashi, 2004; Frank, 2011).

important cause of cardiac transplantation (Sugrue, 1992).

**3. Dilated cardiomyopathy**

2003, Richard, 2006).

108 Cardiomyopathies

Hypertrophic cardiomyopathy (HCM) is a familial disease that in fifty percent of the cases is inherited in an autosomal dominant pattern. The disorder shows complete penetrance in most families although it depends on the age and the sex of the patients (Nimura, 1998, Richard,

As the prevalence of HCM is 1: 500, it can be stated that HCM is undoubtedly the most common

HCM has been traditionally described as an unexplained hypertrophy of the left ventricle that develops in the absence of systemic hypertension, valvular heart disease or amyloidosis. The

The clinical presentation is variable. There can be varying degrees of clinical severity which can range from dyspnea, palpitations, atrial fibrillation, and syncopal episodes to congestive heart failure and sudden death. Many can be asymptomatic throughout their whole life, whereas others may even require heart transplantation. It is the most common cause of death

HCM generally has normal systolic function, impaired diastolic function and outflow ob‐ struction in about 25%. The histopathology shows myocyte disarray, interstitial fibrosis and

Mutations in any of the thirteen sarcomeric genes lead to HCM. (See Table 1). The sarcomere has a complex structure where the proteins that form it interact among themselves. The different mechanisms that cause HCM are not yet completely understood. Most mutations in HCM are private of each family and there is clinical heterogeneity within family members

Dilated cardiomyopathy is the most common cause of congestive heart failure in young patients. The prevalence is ~36: 100,000 in the U.S. It is characterized by ventricular chamber enlargement, thin wall thickness, impaired left ventricular systolic function, and there is also, in some cases, secondary diastolic dysfunction. The most common feature is congestive heart failure, though, conduction impairment, syncope and sudden death may also occur. It is an

The histological findings are nonspecific and they include myocyte loss and interstitial fibrosis. Familial cases of DCM were initially considered to be quite rare. However, careful screenings

In these families, the pattern of inheritance is variable, so the patients present both locus heterogeneity and allellic heterogeneity. Mutations in many genes have been reported to cause

have shown that up to 35% of the probands´ relatives have a DCM familial disorder.

left ventricular hypertrophy (LVH) is usually asymmetric and involves the septum.

different forms of dilated cardiomyopathy. Therefore, autosomal dominant, autosomal recessive, and X-linked inheritance can be observed. (See Table 2) However, the autosomal dominant pattern is the most frequent mode of inheritance. It has been demonstrated that DCM has reduced penetrance. The age of onset shows great variability though it is usually appears in adulthood (Mangin, 1999). When the mutation is in one of the sarcomeric genes the affected patients are usually young adults (Aernout Somsen, 2012).


**DCM gene Symbol Locus name Chromosome locus Protein Mode of**

TNNI3 gene *TNNI3* CMD1FF 19q13.4; Troponin I, AD

SDHA gene *SDHA* CMD1GG 5p15; Succinate dehydrogenase

BAG3 gene *BAG3* CMD1HH 10q25.2-q26.2 BCL2-associated

TNNI3 gene *TNNI3* CMD2A, 19q13.42 Troponin I, cardiac

GATAD1 gene. *GATAD1* CMD2 7q21.2 GATA zinc finger domain

LAMP2 gene *LAMP2* Danon disease Xq24 lysosome-associated

q16; and *CMD1Q* on 7q22.3-q31.1 can also cause DCM.

**Table 2.** Genes tha cause DCM

**4. Restrictive cardiomyopathy**

a grave prognosis (Kaski, 2008.)

(Kushwaha, 1997).

reported to cause RCM,

2000; Olson, 2002; Zang, 2005; Kaski, 2008).

Dystrophin gene *DMD* CMD3B Xp21.2 dystrophin X-linked

TAZ gene *TAZ* Xq28 dystrophin X-linked

Mutations on the following genes *CMD1B* on 9q13; *CMD1H* on 2q14-q22; *CMD1K* on 6q12-

Familial restrictive cardiomyopathy (RCM) is a rare disease which is inherited in autosomal dominant pattern with incomplete penetrance (Katritsis 1991). The exact prevalence of RCM is unknown (Elliott, 2008). In childhood, RCM accounts for 2–5% of cardiomyopathies and has

RCM is characterized by abnornal diastolic function, which has a restrictive filling pattern, a reduced diastolic volume of one of the ventricles or both ventricles, enlargement of the atria, pulmonary hypertension and heart failure. In the early stages of the disorder the systolic function may be normal, but as the disease progresses, the systolic function generally declines

The familial RCM is linked to the cardiac troponin genes. RCM1 is caused by a mutation in the *TNNI3* gene on chromosome 19q13. This gene encodes the cardiac muscle isoform of troponin 1. RCM2 has been mapped to chromosome 10q23. RCM3 is caused by mutation in the *TNNT2* gene. Mutations in the sarcomere gene, alpha-cardiac actin gene (*ACTC*) have also been

In many cases RCM can be observed overlapping with either HCM or DCM. (Kamisago,

**inheritance**

The Role of Genetics in Cardiomyopathy http://dx.doi.org/10.5772/55775

AD

111

AD

AR

AR

X-linked

complex subunit A

containing protein 1

membrane protein-2

athanogene 3

muscle


**Table 2.** Genes tha cause DCM

**DCM gene Symbol Locus name Chromosome locus Protein Mode of**

Lamin A/C gene *LMNA* CMD1A 1q21 lamin A and lamin C AD

TTN gene *TTN* CMD1G 2q31 Titin AD DES gene *DES* CMD1I 2q35 Desmin AD EYA4 gene *EYA4* CMD1J 6q23-q24 Eyes absent homolog 4 AD SGCD gene *SGCD* CMD1L 5q33 Delta-sarcoglycan AD

TCAP gene *TCAP* CMD1N 17q12; Telethonin AD

PLN gene *PLN* CMD1P on 6q22.1;, Cardiac phospholamban AD

MYH7 gene *MYH7* CMD1S 14q12; Myosin 7 AD TMPO gene *TMPO* CMD1T 12q22 Hymopoietin AD PSEN1 gene *PSEN1* CMD1U 14q24.3 Presenilin-1 AD PSEN2 gene *PSEN2* CMD1V 1q31-q42; Presenilin-2 AD metavinculin VCL CMD1W 10q22-q23 metavinculin VCL AD fukutin *FKTN* CMD1X 9q31 Fukutin AD TPM1 gene *Fukutin* CMD1Y 15q22.1 tropomyosin-1 AD TNNC1 gene *TNNC1* CMD1Z 3p21.3-p14.3 slow troponin-C AD ACTN2 gene *ACTN2* CMD1AA 1q42-q43; Alpha-actinin-2 AD DSG2 gene *DSG2* CMD1BB 18q12.1-q12.2; desmoglein-2 AD NEXN gene *NEXN* CMD1CC 1p31.1 Nelin AD

protein 3

muscle

protein 3

muscle 1

protein 20

subfamily C, member 9

type 5 subunit alpha

LDB3 gene CMD1C 10q22-q23 LIM domain-binding

110 Cardiomyopathies

TNNT2 gene *TNNT2* CMD1D 1q32 Troponin T, cardiac

SCN5A CMD1E 3p Sodium channel protein

CSRP3 gene *CSRP3* CMD1M 11p15.1 Cysteine and glycine-rich

ABCC9 gene CMD1O, on 12p12.1; ATP-binding cassette,

ACTC1 gene *ACTC1* CMD1R 15q14 Actin, alpha cardiac

RBM20 gene *RBM20* CMD1DD 10q25.2; RNA-Binding motif

MYH6 gene *MYH6* CMD1EE 14q12 Myosin 7 AD

**inheritance**

AD

AD

AD

AD

AD

AD

AD

Mutations on the following genes *CMD1B* on 9q13; *CMD1H* on 2q14-q22; *CMD1K* on 6q12 q16; and *CMD1Q* on 7q22.3-q31.1 can also cause DCM.
