*5.2.1 Family screening in case of a known mutation*

In many European countries including Sweden, the physician has no legal right to contact or inform first-degree relatives about the results of a genetic test. Instead the patient must be equipped with sufficient knowledge, both verbally and in written form to inform relatives about the genetic aspect of the disease, although usually there is no legal obligation for the patient to do this.

If the proband, the first identified individual with DCM in a family, has a known disease-causing mutation it is possible to screen all first-degree relatives for this single mutation [13]. If the inheritance pattern is autosomal dominant, children each have 50% risk of carrying the mutation. A simple genetic test could with certainty confirm or reject that an individual carries the mutation, this has large implications. If the individual is not a carrier of the mutated gene, no further follow-up is required, no cascade screening is needed of this individual's children, and the individual have a better chance of living a normal life.

If instead the gene test confirms that an individual carries the mutated gene, so called cascade screening should be considered of this individual's first-degree relatives. Carrying a known disease-causing mutation implies that cardiologic evaluation should be conducted consisting of at least 12-lead ECG and echocardiography. If this evaluation results in a diagnosis of DCM life-long follow-up is required. If this cardiologic evaluation is inconclusive or finds no signs of DCM continued follow-up is still required. The penetrance of familial DCM is most often age-dependent, age at diagnosis of DCM is most often seen during or after puberty up until 60 years of age [13]. Therefore, renewed assessment with at least ECG and echocardiography should be conducted every year between the ages of 10 and 20 and then every 1–3 years.

#### *5.2.2 Family screening in case of no known mutation*

In idiopathic DCM, in a setting where genetic testing is not available, negative, or inconclusive, familial DCM can still not be ruled out. All first-degree relatives of the proband should undergo cardiologic evaluation with at least 12-lead ECG and echocardiography [13]. If they are diagnosed with DCM life-long follow-up is required and all their first-degree relatives should undergo cardiologic evaluation as well. If instead the cardiologic evaluation is negative for DCM, the relative should be followed-up with repeat cardiologic evaluations; every 1–3 years for those younger than 10 years of age, every 1–2 years between the age of 10 and 20, and every 2–5 years from 20 years of age up until 50–60 years of age. The reason for this continued evaluation during life is the age-dependent penetrance. For those affected, penetrance is almost complete at 60 years of age, therefore repeated evaluation is not necessary after this [13].

#### **6. Causative gene mutations**

Many genes have been linked to DCM, some with a definite and some with a putative link. For definite DCM genes see **Table 1**, adapted from McNally et al. [22]. It is often difficult to determine if a mutation in a gene is causative of cardiomyopathy, sometimes mutations are determined to be so called variants of unknown significance. Most genes implicated in the pathogenesis of DCM are highly conserved with few *de novo* mutations occurring, making new mutations, found in a known DCM gene that alters the encoded protein, likely to be pathogenic.

Mutations that have been linked to DCM affect genes related to diverse cell structures such as; ion channels, dystrophin complexes, sarcoplasmic reticulum, nuclear lamina, desmosomes, mitochondria, cytoskeleton, z-disc, and sarcomeres. For an image visualizing different cellular structures related to definite DCM genes see **Figure 3**.

#### **6.1 Genes associated with sudden cardiac death**

The general consensus is that risk of arrhythmia in DCM scales with the degree of left ventricular systolic dysfunction. Most genotypes cannot be distinguished from each other by evaluation of the phenotype. Due to this broad gene panels are required. However, some genotypes have been shown to be prone to arrhythmia and in some

**179**

*Familial Dilated Cardiomyopathy: Risk Stratification for Sudden Cardiac Death*

ACTC1 Alpha cardiac actin HCM, LVNC

TNNC1 Cardiac troponin C HCM, LVNC TNNI3 Cardiac troponin 1 HCM

**Z-disc Mechanosensing/mechanosignaling** ACTN2 Alpha-actinin 2 LVNC

**Gene Protein Frequency and overlapping phenotypes**

MYH7 Beta-myosin heavy chain 3–4% of DCM; HCM, LVNC TPM1 Alpha-tropomyosin 1–2% of DCM; HCM, LVNC

TNNT2 Cardiac troponin T 3% of DCM; HCM, LVNC

BAG3 BCL2 Associated Athanogene 3 Myofibrillar myopathy CRYAB Alpha-B-crystallin Protein aggregation myopathy

ANKRD1 Cardiac ankyrin repeat protein Congenital heart disease

**Cytoskeleton Mechanotransduction/mechanosignaling/structural integrity**

**Desmosomes Cell–cell adhesion/mechanotransmission/mechanosignaling** DSP Desmoplakin 2% of DCM; ARVC

**Sarcoplasmic reticulum and cytoplasm Ca homeostasis, contractility modulation, signaling**

**Nuclear envelope Nuclear structural integrity, mechanotransduction, mechanosignaling** LMNA Lamin A/C 4–8% of DCM; multiple phenotypes,

RBM20 RNA-binding protein 20 2% of DCM; RNA-binding protein of

DMD Dystrophin Duchenne/Becker muscular dystrophy

DES Desmin <1% of DCM; desminopathies, myofibrillar

FLNC Filamin C 1% of DCM; myofibrillar myopathy, HCM,

TCAP Titin-cap/telethonin LGMD2G CSRP3 Muscle LIM protein HCM

LDB3 Cipher/ZASP LVNC NEBL Nebulette LVNC, HCM

SGCA Alpha-sarcoglycan LGMD2D SGCB Beta-sarcoglycan LGMD2E SGCD Delta-sarcoglycan LGMD2F

VCL Metavinculin 1% of DCM

PLN Phospholamban ARVC, HCM

EMD Emerin EDMD **Nucleus Transcription cofactors, gene expression**

**Ion channels Transportation of ions**

SCN5A Type V voltage-gated cardiac Na channel

**Dystrophin complex Sarcolemma, structural integrity**

TTN Titin 12–25% of DCM; HCM, tibial muscle

TNNI3K Troponin 1 interacting kinase Conduction defect, atrial fibrillation

dystrophy

myopathy

RCM

LGMD1B, EDMD, progeria

spliceosome of TTN and other proteins

2–3% of DCM; LQTS, Brugada, atrial fibrillation, conduction defects

*DOI: http://dx.doi.org/10.5772/intechopen.94437*

**Sarcomere Force generation/transmission**


*Sudden Cardiac Death*

for this single mutation [13]. If the inheritance pattern is autosomal dominant, children each have 50% risk of carrying the mutation. A simple genetic test could with certainty confirm or reject that an individual carries the mutation, this has large implications. If the individual is not a carrier of the mutated gene, no further follow-up is required, no cascade screening is needed of this individual's children,

If instead the gene test confirms that an individual carries the mutated gene, so called cascade screening should be considered of this individual's first-degree relatives. Carrying a known disease-causing mutation implies that cardiologic evaluation should be conducted consisting of at least 12-lead ECG and echocardiography. If this evaluation results in a diagnosis of DCM life-long follow-up is required. If this cardiologic evaluation is inconclusive or finds no signs of DCM continued follow-up is still required. The penetrance of familial DCM is most often age-dependent, age at diagnosis of DCM is most often seen during or after puberty up until 60 years of age [13]. Therefore, renewed assessment with at least ECG and echocardiography should be conducted every year between the ages of 10 and 20 and then every 1–3 years.

In idiopathic DCM, in a setting where genetic testing is not available, negative, or inconclusive, familial DCM can still not be ruled out. All first-degree relatives of the proband should undergo cardiologic evaluation with at least 12-lead ECG and echocardiography [13]. If they are diagnosed with DCM life-long follow-up is required and all their first-degree relatives should undergo cardiologic evaluation as well. If instead the cardiologic evaluation is negative for DCM, the relative should be followed-up with repeat cardiologic evaluations; every 1–3 years for those younger than 10 years of age, every 1–2 years between the age of 10 and 20, and every 2–5 years from 20 years of age up until 50–60 years of age. The reason for this continued evaluation during life is the age-dependent penetrance. For those affected, penetrance is almost complete at

60 years of age, therefore repeated evaluation is not necessary after this [13].

Many genes have been linked to DCM, some with a definite and some with a putative link. For definite DCM genes see **Table 1**, adapted from McNally et al. [22]. It is often difficult to determine if a mutation in a gene is causative of cardiomyopathy, sometimes mutations are determined to be so called variants of unknown significance. Most genes implicated in the pathogenesis of DCM are highly conserved with few *de novo* mutations occurring, making new mutations, found in a known DCM gene that alters the encoded protein, likely to be pathogenic.

Mutations that have been linked to DCM affect genes related to diverse cell structures such as; ion channels, dystrophin complexes, sarcoplasmic reticulum, nuclear lamina, desmosomes, mitochondria, cytoskeleton, z-disc, and sarcomeres. For an image visualizing different cellular structures related to definite DCM genes

The general consensus is that risk of arrhythmia in DCM scales with the degree of left ventricular systolic dysfunction. Most genotypes cannot be distinguished from each other by evaluation of the phenotype. Due to this broad gene panels are required. However, some genotypes have been shown to be prone to arrhythmia and in some

and the individual have a better chance of living a normal life.

*5.2.2 Family screening in case of no known mutation*

**6.1 Genes associated with sudden cardiac death**

**6. Causative gene mutations**

**178**

see **Figure 3**.


*ARVC: arrhythmogenic right ventricular cardiomyopathy; DCM: dilated cardiomyopathy; EDMD: Emery Dreifuss muscular dystrophy; HCM: hypertrophic cardiomyopathy; LGMD: limb-girdle muscular dystrophy; LVNC: left ventricular non-compaction cardiomyopathy; LQTS: long QT-syndrome; RCM: restrictive cardiomyopathy. Adapted from McNally et al. [22].*

#### **Table 1.**

*Definite dilated cardiomyopathy genes.*

#### **Figure 3.**

*Cross section of two cardiomyocytes that connect to each other with desmosomes at the intercalated disc. Definite DCM genes and important cellular structures pertaining to them are named. Image by Todd Cooper.*

cases sudden cardiac death. Some genes are very rare, or only putative and not definitively linked to DCM. Out of the genes that regularly are found to cause DCM, LMNA and SCN5A stand out for their propensity to cause arrhythmia. Mutations in both of these genes can cause a phenotype with atrial fibrillation, conduction system disease or ventricular tachyarrhythmia as the presenting symptom [22]. Guidelines from the ESC give specific indications for the implantation of an ICD in patients with DCM and LMNA mutation, these are described below [3]. For SCN5A no specific guidelines are given [3]. However, it is reasonable to adapt clinical management for patients with mutation in this gene to account for the known risk for arrhythmia. This also holds true for patients with other or unknown mutations, but with a family history indicative of a high risk of arrhythmia and sudden cardiac death. Such adaptations might include more frequent ambulatory ECG-monitoring or the use of insertable cardiac monitors to screen for potentially life-threatening arrhythmias.

## *6.1.1 LMNA*

LMNA, the gene encoding the proteins lamin A and C, is one of the most studied DCM genes. Lamin A/C form part of the nuclear lamina and have been implicated in several cellular processes, including regulation of gene expression [22]. DCM

**181**

**8. Conclusion**

*6.1.2 SCN5A*

**7. Future perspectives**

*Familial Dilated Cardiomyopathy: Risk Stratification for Sudden Cardiac Death*

cardiomyopathy may be caused by ventricular tachyarrhythmias [24].

Mutations in SCN5A, the gene that encodes the sodium voltage-gated channel alpha subunit 5 involved in the main cardiac sodium channel, has been linked to several diseases including Brugada syndrome, long QT-syndrome as well as DCM and ARVC [25]. Different kinds of mutations in SCN5A have been linked to DCM and the mechanism is still uncertain. Interestingly, the phenotype varies in families with the same genotype, indicating that environmental or other confounding factors are at play [25]. Mutations in SCN5A have also been linked to progressive conduction disorder and familial atrial fibrillation. Given this, it is not surprising that DCM due to SCN5A often presents with increased risk of arrhythmia [22].

Currently, familial DCM is likely frequently underdiagnosed, and often genetic testing is not conducted. Increased awareness and availability of genetic evaluation might provide more knowledge and gene-specific therapies and management might become available. Increased identification of affected families will mean that more at-risk individuals will come into contact with health care providers prior to developing the phenotype. This means that future studies should focus on therapies aimed to prevent the development of DCM in these individuals. Further research into the different genotypes and their burden of arrhythmia is also warranted in order to improve risk stratification for sudden cardiac death. This includes the utilization of implantable cardiac monitors in those patients who have certain high-risk genotypes but have been judged not to fulfill criteria for the implantation of an ICD.

Reduced left ventricular systolic ejection fraction is the most common indication for the implantation of an ICD regardless of type of cardiomyopathy. In DCM some

associated with mutation in LMNA tend to have age-dependent penetrance but with disease onset early in life, often dysrhythmias mainly conduction disturbances and atrial fibrillation precede the development of heart failure. The risk for sudden cardiac death is also increased, even with only moderately reduced left ventricular ejection fraction [3]. Guidelines of the ESC state that an ICD should be considered (class of recommendation IIa) for patients with DCM and a confirmed diseasecausing mutation in LMNA if any of the following clinical risk factors are present; non-sustained ventricular tachycardia, left ventricular ejection fraction ≤45%, male sex, or a non-missense mutation (insertion, deletion, truncation or mutation affecting splicing) [3]. This recommendation is based upon the results of a cohort study of 269 patients with LMNA-mutation and a median follow-up time of 43 months, 48 patients (18%) reached the composite endpoint of sudden cardiac death, appropriate ICD therapy, or aborted cardiac death [23]. In a review of published cohorts of patients with LMNA-associated cardiomyopathy, in total 299 patients, some sort of dysrhythmia was reported in 92% after the age of 30 years [24]. Dysrhythmias included sinus bradycardia, first-degree AV-block, and atrial or ventricular tachyarrhythmias [24]. Notably, almost half died from sudden cardiac death [24]. This high proportion of sudden cardiac death was also noted in those patients who had a pacemaker implanted, which implies that the mode of death in LMNA-associated

*DOI: http://dx.doi.org/10.5772/intechopen.94437*

#### *Familial Dilated Cardiomyopathy: Risk Stratification for Sudden Cardiac Death DOI: http://dx.doi.org/10.5772/intechopen.94437*

associated with mutation in LMNA tend to have age-dependent penetrance but with disease onset early in life, often dysrhythmias mainly conduction disturbances and atrial fibrillation precede the development of heart failure. The risk for sudden cardiac death is also increased, even with only moderately reduced left ventricular ejection fraction [3]. Guidelines of the ESC state that an ICD should be considered (class of recommendation IIa) for patients with DCM and a confirmed diseasecausing mutation in LMNA if any of the following clinical risk factors are present; non-sustained ventricular tachycardia, left ventricular ejection fraction ≤45%, male sex, or a non-missense mutation (insertion, deletion, truncation or mutation affecting splicing) [3]. This recommendation is based upon the results of a cohort study of 269 patients with LMNA-mutation and a median follow-up time of 43 months, 48 patients (18%) reached the composite endpoint of sudden cardiac death, appropriate ICD therapy, or aborted cardiac death [23]. In a review of published cohorts of patients with LMNA-associated cardiomyopathy, in total 299 patients, some sort of dysrhythmia was reported in 92% after the age of 30 years [24]. Dysrhythmias included sinus bradycardia, first-degree AV-block, and atrial or ventricular tachyarrhythmias [24]. Notably, almost half died from sudden cardiac death [24]. This high proportion of sudden cardiac death was also noted in those patients who had a pacemaker implanted, which implies that the mode of death in LMNA-associated cardiomyopathy may be caused by ventricular tachyarrhythmias [24].

#### *6.1.2 SCN5A*

*Sudden Cardiac Death*

*from McNally et al. [22].*

*Definite dilated cardiomyopathy genes.*

**Table 1.**

**Figure 3.**

ABCC9 Component of ATP-sensitive

potassium channel

**Mitochondria Supply and/or regulation of energy metabolism**

**180**

*6.1.1 LMNA*

cases sudden cardiac death. Some genes are very rare, or only putative and not definitively linked to DCM. Out of the genes that regularly are found to cause DCM, LMNA and SCN5A stand out for their propensity to cause arrhythmia. Mutations in both of these genes can cause a phenotype with atrial fibrillation, conduction system disease or ventricular tachyarrhythmia as the presenting symptom [22]. Guidelines from the ESC give specific indications for the implantation of an ICD in patients with DCM and LMNA mutation, these are described below [3]. For SCN5A no specific guidelines are given [3]. However, it is reasonable to adapt clinical management for patients with mutation in this gene to account for the known risk for arrhythmia. This also holds true for patients with other or unknown mutations, but with a family history indicative of a high risk of arrhythmia and sudden cardiac death. Such adaptations might include more frequent ambulatory ECG-monitoring or the use of insertable cardiac

*Cross section of two cardiomyocytes that connect to each other with desmosomes at the intercalated disc. Definite* 

*DCM genes and important cellular structures pertaining to them are named. Image by Todd Cooper.*

**Gene Protein Frequency and overlapping phenotypes**

KCNQ1 Potassium channel Atrial fibrillation, LQTS1, short QT1, Jervell

DNAJC19 HSP40 homolog, C19 3-methylglutaconic aciduria type V TAZ/G4.5 Tafazzin LVNC, Barth syndrome, endocardial

*ARVC: arrhythmogenic right ventricular cardiomyopathy; DCM: dilated cardiomyopathy; EDMD: Emery Dreifuss muscular dystrophy; HCM: hypertrophic cardiomyopathy; LGMD: limb-girdle muscular dystrophy; LVNC: left ventricular non-compaction cardiomyopathy; LQTS: long QT-syndrome; RCM: restrictive cardiomyopathy. Adapted* 

Atrial fibrillation, osteochondrodysplasia

and Lange-Nielsen syndrome

fibroelastosis 2

LMNA, the gene encoding the proteins lamin A and C, is one of the most studied DCM genes. Lamin A/C form part of the nuclear lamina and have been implicated in several cellular processes, including regulation of gene expression [22]. DCM

monitors to screen for potentially life-threatening arrhythmias.

Mutations in SCN5A, the gene that encodes the sodium voltage-gated channel alpha subunit 5 involved in the main cardiac sodium channel, has been linked to several diseases including Brugada syndrome, long QT-syndrome as well as DCM and ARVC [25]. Different kinds of mutations in SCN5A have been linked to DCM and the mechanism is still uncertain. Interestingly, the phenotype varies in families with the same genotype, indicating that environmental or other confounding factors are at play [25]. Mutations in SCN5A have also been linked to progressive conduction disorder and familial atrial fibrillation. Given this, it is not surprising that DCM due to SCN5A often presents with increased risk of arrhythmia [22].
