**12. The impact of genetics in the understanding of cardiomyopathy**

The different mitochondrial cardiomyopathies are a result of the heart being commonly affected. Sometimes, the cardiomyopathy is diagnosed during the first year of life even before the mitochondrial disorder has been diagnosed. Both hypertrophic and dilated cardiomyopa‐

**locus**

*SGCG* SGCG 13q12-q13 gamma

*SGCA* SGCA 17q21 Alpha

*SGCB* SGCB 4q12 Beta

*SGCD* SGCD 5q33-q34 Delta

*FKRP* FKRP 19q13.32 fukutin related

**Protein Mode of**

sarcoglycan

sarcoglycan

sarcoglycan

sarcoglycan

protein

**inheritance**

AR

AR

AR

AR

AR

The Kearns-Sayre syndrome (KSS) is characterized by the triad: onset of the disorder before the age of 20, progressive external ophthalmoplegia and pigmentary retinopathy. A cerebro‐ spinal fluid protein concentration greater than 100 mg/d, and a commonly elevated lactate and

The KSS has cardiac involvement with conduction defects such as right bundle branch block, left anterior hemiblock or complete A-V block. These patients can develop a cardiomyopathy

It is a multisystem disorder with onset in childhood with mitochondrial encephalomyopathy, lactic acidosis, and recurrent stroke-like episodes. The variability of symptoms and the severity of the syndrome make it difficult to confirm the diagnosis. MELAS is transmitted by maternal

thies have been reported (Holmgren, 2003, de Jonge, 2011).

**Disease Name Gene Symbol Locus name Chromosome**

pyruvate concentrations in blood and cerebrospinal fluid are found.

usually dilated (Roberts, 1979; Anan, 1995; Carrasco, 2005).

**11. Kearns-Sayre syndrome**

LGMD2C gamma

118 Cardiomyopathies

LGMD2D alpha

LGMD2E Beta

LGMD2F Delta

LGMD2I fukutin related

sarcoglycan gene

sarcoglycan gene

sarcoglycan gene

sarcoglycan gene

protein gene

**Table 5.** Limb-girdle muscular dystrophies

**11.1. MELAS**

inheritance.

Although the diagnosis is based primarily on DNA analysis, a thorough clinical history and examination, blood tests, the ECG, echocardiography, electromyography, and muscle biopsy can also provide information that can be helpful for the diagnosis not only of the patients, but also of the asymptomatic carriers.

With the expansion in number of the different disorders that have myocardial involvement in conjunction with the development of their molecular and biochemical bases, it can be stated that these will play a most important role in the understanding of the pathophysiology of the syndromes.

The exact role and function each mutated protein has and the pathogenic mechanisms that lead to the different disorders still have to be elucidated, in spite of the fact that the mutations that cause them have been found.

It has also been observed that the mutations within the same gene and in the same family can give rise to distinct phenotypes in HCM, DCM and RCM. The pathogenesis of the three major types of cardiomyopathy can be linked to the the genetic mutations in the different sarcomeric proteins. These gene mutations are responsible to trigger the different pathways that lead to the remodeling of the heart. The mechanisms why this occurs are still unclear and the animal models are markedly distinct.

Since HCM is an autosomal dominant disorder most of the patients suffering from it are heterozygous. Mutations in MYH7 and/or MYBPC3 genes account for 80% of the mutations (Richard, 2006).

As soon as the patients are diagnosed with the myopathies mentioned above they should be cardiologically checked-up, and should be treated immediately as the cardiac therapy

The Role of Genetics in Cardiomyopathy http://dx.doi.org/10.5772/55775 121

In Timothy syndrome the molecular diagnosis of *CACNA1C* should be performed in several

It has been observed that mutations in the lamin A/C gene cause CMD1A, LGMD1B or EDMD2

The mitochondrial deletion syndromes are generally not inherited. The *de novo* deletions that take place in the mother's oocytes during germline development or in the embryo during embryogenesis are to be held responsible for these syndromes. 90% of the patients with KSS have deletions of mtDNA. The deletions are present in all tissues in individuals with KSS. There is no correlation between the size or the location of the mtDNA deletion and the

It has suggested that the mutations in the nuclear gene *RRM2B* gene cause cause KSS following a Mendelian mode of inheritance. The patient had multiple mtDNA deletions and a normal left ventricular function with an increased thickness of the interventricular septum and left

Approximately 80% of cases of MELAS are due to mutations in the mtDNA gene *MT-TL1* which encodes tRNA leucine. The mutations in *MT-ND5* gene which encodes the NADHubiquinone oxidoreductase subunit 5 have also been found in individuals with MELAS or with

To provide genetic counseling to an individual that has a cardiomyopathy is not an easy task. When a patient or a relative that has been diagnosed with cardiomyopathy comes for genetic counseling, the geneticist has to be forthright and explain that there are all sorts of disorders

It is very important that when a numerical value is provided the patient and/or his family understand what has been explained to them. It is necessary to be very clear that chance does not have a memory. It would be embarrassing to face a family that comes with a second affected

It should also be pointed out that the molecular diagnosis of a disorder it is not only time consuming and a very expensive process, but also that, sometimes, there is not a specific mutation that stands out in the different disorders that cause a cardiomyopathy. Many patients

Opinions differ about procedures when consultants are under 18 and asymptomatic, and at risk of having the disorder when adults, and there is not a causal treatment. Therefore, running

phenotype and penetrance because there are related to the mutation load.

**13. What should the genetic counseling be in cardiomyopathy?**

child because they have misinterpreted the information provided to them.

improves the cardiac involvement and life expectancy

in the same family (Becane, 2000; Brodsky, 2000)

posterior ventricular wall (Pitceathly, 2012).

that cause it, locus heterogeneity and clinical variability.

do not have an identified causing gene defect.

overlap syndromes (Di Mauro,2005).

tissues, including sperm.

In some cases, patients have two different mutations, usually in *MYH7* and/or *MYBPC3* genes. These mutations result in the patients being compound heterozygous. The double heterozy‐ gotes that have also been observed have mutations in the *MyBP-C/ β –MHC*, *MyBP-C/ TNNT2*, *MyBP-C/TNNT3*, *MyBP-C/TPM*, *β-MHC/TNNT2* genes. Sometimes, the patients can be homozygous for a mutation in the genes *MyBP-C, β -MHC*, and *TNNT2* (Richard, 1999; Richard 2003; Van Driest, 2004; Ingles, 2005; Richard 2006).

The genotype-phenotype correlations have been linked to specific mutations (Richard, 2006).

The different mutations in the *MYH7*gene show great variability in symptomatology. Patients with the R403Q, R719W and R719Q mutations have complete penetrance, severe hypertrophy and short life expectancy, whereas those with the V606M mutation have a mild progression (Ho, 2000; Richard, 2006; Overeem, 2007; Uro-Coste, 2009).

All the patients that have mutations in the *TNNT2* gene seem to have a more severe course. In most cases, the affected patients carrying the mutations R92W, R92Q, I79N are young, and even though they have a mild LVH, they died of sudden death. The F110I mutation does not seem to have a so severe development as the rest of the mutations in this gene (Watkins, 1995; Arian, 1998; Tardiff, 2005, Richard, 2006).

It is believed that patients having double mutations have a greater severity of the disorder due to a double dose effect (Ingles, 2005).

Incomplete or reduced penetrance has been observed in many cases (20 to 30%) as there are parents that are carriers of the mutations, but they have not developed the disease. It is unknown whether carriers will develop the disorder at a certain age of their lives or will remain asymptomatic. Symptoms show a great variability among the patients that have the same mutation and suffer the disorder. These may be due to gene interaction, environmental factors and modifier genes (Michels, 1992; Mestroni, 1999; Criley, 2003; Richard, 2006).

In many cases RCM can be observed overlapping with either HCM or DCM. An autosomal dominant cardiomyopathy has been described where the single sarcomere *TNNT2* gene mutation can cause idiopathic RCM in some patients, or HCM or DCM in others.

All affected members of a RCM-associated family have the I79N mutation in the *TNNT2* gene, thus showing the variability of the disorders (Peddy, 2006; Menon, 2008).

It is very difficult to assess the genotype-phenotype correlation in NCCM. It seems that when there are mutations in the alpha-dystrobrevin gene (*DTNA)* on chromosome 18q12.1 and taffazin gene (*TAZ)* on chromosome Xq28 (Bleyt, 1997). It has been observed that when the mutations are in a sarcomeric gene, they give rise to a truncated protein and the onset of the disorder is during childhood. When there is an adult onset, there can be multiple mutations in a non sarcomeric gene thus the phenotype is more severe

As soon as the patients are diagnosed with the myopathies mentioned above they should be cardiologically checked-up, and should be treated immediately as the cardiac therapy improves the cardiac involvement and life expectancy

Since HCM is an autosomal dominant disorder most of the patients suffering from it are heterozygous. Mutations in MYH7 and/or MYBPC3 genes account for 80% of the mutations

In some cases, patients have two different mutations, usually in *MYH7* and/or *MYBPC3* genes. These mutations result in the patients being compound heterozygous. The double heterozy‐ gotes that have also been observed have mutations in the *MyBP-C/ β –MHC*, *MyBP-C/ TNNT2*, *MyBP-C/TNNT3*, *MyBP-C/TPM*, *β-MHC/TNNT2* genes. Sometimes, the patients can be homozygous for a mutation in the genes *MyBP-C, β -MHC*, and *TNNT2* (Richard, 1999;

The genotype-phenotype correlations have been linked to specific mutations (Richard, 2006).

The different mutations in the *MYH7*gene show great variability in symptomatology. Patients with the R403Q, R719W and R719Q mutations have complete penetrance, severe hypertrophy and short life expectancy, whereas those with the V606M mutation have a mild progression

All the patients that have mutations in the *TNNT2* gene seem to have a more severe course. In most cases, the affected patients carrying the mutations R92W, R92Q, I79N are young, and even though they have a mild LVH, they died of sudden death. The F110I mutation does not seem to have a so severe development as the rest of the mutations in this gene (Watkins,

It is believed that patients having double mutations have a greater severity of the disorder due

Incomplete or reduced penetrance has been observed in many cases (20 to 30%) as there are parents that are carriers of the mutations, but they have not developed the disease. It is unknown whether carriers will develop the disorder at a certain age of their lives or will remain asymptomatic. Symptoms show a great variability among the patients that have the same mutation and suffer the disorder. These may be due to gene interaction, environmental factors

In many cases RCM can be observed overlapping with either HCM or DCM. An autosomal dominant cardiomyopathy has been described where the single sarcomere *TNNT2* gene

All affected members of a RCM-associated family have the I79N mutation in the *TNNT2* gene,

It is very difficult to assess the genotype-phenotype correlation in NCCM. It seems that when there are mutations in the alpha-dystrobrevin gene (*DTNA)* on chromosome 18q12.1 and taffazin gene (*TAZ)* on chromosome Xq28 (Bleyt, 1997). It has been observed that when the mutations are in a sarcomeric gene, they give rise to a truncated protein and the onset of the disorder is during childhood. When there is an adult onset, there can be multiple mutations

and modifier genes (Michels, 1992; Mestroni, 1999; Criley, 2003; Richard, 2006).

mutation can cause idiopathic RCM in some patients, or HCM or DCM in others.

thus showing the variability of the disorders (Peddy, 2006; Menon, 2008).

in a non sarcomeric gene thus the phenotype is more severe

Richard 2003; Van Driest, 2004; Ingles, 2005; Richard 2006).

(Ho, 2000; Richard, 2006; Overeem, 2007; Uro-Coste, 2009).

1995; Arian, 1998; Tardiff, 2005, Richard, 2006).

to a double dose effect (Ingles, 2005).

(Richard, 2006).

120 Cardiomyopathies

In Timothy syndrome the molecular diagnosis of *CACNA1C* should be performed in several tissues, including sperm.

It has been observed that mutations in the lamin A/C gene cause CMD1A, LGMD1B or EDMD2 in the same family (Becane, 2000; Brodsky, 2000)

The mitochondrial deletion syndromes are generally not inherited. The *de novo* deletions that take place in the mother's oocytes during germline development or in the embryo during embryogenesis are to be held responsible for these syndromes. 90% of the patients with KSS have deletions of mtDNA. The deletions are present in all tissues in individuals with KSS. There is no correlation between the size or the location of the mtDNA deletion and the phenotype and penetrance because there are related to the mutation load.

It has suggested that the mutations in the nuclear gene *RRM2B* gene cause cause KSS following a Mendelian mode of inheritance. The patient had multiple mtDNA deletions and a normal left ventricular function with an increased thickness of the interventricular septum and left posterior ventricular wall (Pitceathly, 2012).

Approximately 80% of cases of MELAS are due to mutations in the mtDNA gene *MT-TL1* which encodes tRNA leucine. The mutations in *MT-ND5* gene which encodes the NADHubiquinone oxidoreductase subunit 5 have also been found in individuals with MELAS or with overlap syndromes (Di Mauro,2005).
