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University of Groningen
Inherited Cardiomyopathies
Spaendonck-Zwarts, Karin Yvon van
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Spaendonck-Zwarts, K. Y. V. (2014). Inherited Cardiomyopathies: Genetics and Gene-Environment
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1
General introduction and outline
of this thesis
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Chapter 1
GENERAL INTRODUCTION
Inherited Cardiomyopathies
Cardiomyopathies are defined as myocardial disorders in which the heart is structurally and
functionally abnormal in the absence of coronary artery disease, valvular heart disease, hypertension, or congenital heart disease sufficient to cause the observed myocardial abnormality.1
Cardiomyopathies are grouped by the European Society of Cardiology into four main subtypes
based on ventricular morphology and physiology: hypertrophic cardiomyopathy (HCM),
dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM), and arrhythmogenic right
ventricular cardiomyopathy (ARVC). Those cases that do not readily fit into these subtypes are
called “unclassified cardiomyopathies”, including left ventricular non-compaction cardiomyopathy (LVNC), endocardial fibroelastosis, and Tako-Tsubo cardiomyopathy. Each subtype of
cardiomyopathy is subdivided into familial/genetic and non-familial/non-genetic forms.1
The inheritance pattern of inherited cardiomyopathies is most commonly autosomal dominant, but autosomal recessive, X-linked and mitochondrial inheritance patterns have also been
observed. Incomplete, age-related penetrance and variable expression are typical features of
inherited cardiomyopathies. Incomplete penetrance implies that some mutation carriers will
remain unaffected throughout their entire life. Age-related penetrance implies that the proportion of mutation carriers with associated symptoms (phenotype) increases with age. The
onset of symptoms is usually in the second or third decade of life and often even later, but
children with severe forms of inherited cardiomyopathies have been described. Some of these
cases have been associated with multiple underlying mutations that, taken alone, are associated
with late onset cardiomyopathy.2,3 Variable expression refers to differences in both features
and severity of disease between individuals carrying the same mutation, even within the same
family. Inherited cardiomyopathies are not only clinically variable; the genetic causes are also
heterogeneous. In the last two decades, more than 60 genes involved in inherited cardiomyopathies have been identified. For each cardiomyopathy subtype, multiple disease genes are known.
Mutations in several genes, especially in those genes coding for sarcomeric proteins, can cause
different cardiomyopathy subtypes (Figure 1). The genetic overlap can consist of different
mutations in the same gene resulting in different cardiomyopathy subtypes, for example due to
different functional consequences of the mutations,6 but identical mutations are also described
to be associated with different cardiomyopathy subtypes, even within a single family.7
The cardiomyopathy classification is in some cases limited. Due to heterogeneous clinical and
morphological expression of these disorders, patients may fulfill the criteria of more than one
subtype. Clinical management differs between cardiomyopathy subtypes and focuses on different
clinical disease consequences, like the risk of malignant ventricular arrhythmias. But clinical
practice should, in some cases, also be guided by the genetic cause of cardiomyopathy. Identification of a specific cause for a cardiomyopathy can directly influence management of patients
and their relatives. For instance, LMNA mutations are associated with a high risk of sudden
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cardiac death, even before the occurrence of overt DCM, so that an implantable cardioverter
defibrillator is recommended based on a genotype-specific algorithm.8 In 2012, the ESC Working
Group on Myocardial and Pericardial diseases published a position statement for the clinical approach to diagnosis of cardiomyopathies.9 When considering genetic testing and family
screening, it is of utmost importance to offer genetic counseling to the patients and their relatives, in order to help individuals deal with the psychological, social, professional, ethical, and
legal implications of a genetic disease.10
Dilated Cardiomyopathy
Dilated cardiomyopathy (DCM) is defined as a myocardial disorder characterized by the presence of left ventricular (LV) dilatation and LV systolic impairment in the absence of abnormal
loading conditions (e.g. hypertension, valve disease) or coronary artery disease sufficient to
cause global systolic dysfunction.1 Right ventricular dilatation and dysfunction may also be
present. The prevalence of DCM was previously thought to be in the range of 1 in 2,500
adults, but this is undoubtedly a substantial underestimate. In a recent review it has even been
estimated to be in the range of 1 in 250 adults.11 In children, the prevalence is much lower. The
symptoms and signs associated with DCM are highly variable and depend on the degree of LV
dysfunction. The majority of patients present with symptoms of high pulmonary venous pressure and/or low cardiac output (“heart failure”), whilst sudden cardiac death or a thromboembolic event may be the initial presentation. The presentation can be acute or chronic, and may
precede the diagnosis by many months or years. DCM can also be diagnosed in asymptomatic
individuals as a result of family screening. DCM may occur with or without associated cardiac
conduction disease (CCD). In some cases, there may also be neuromuscular involvement. The
prognosis of DCM is variable and depends on the presentation and etiology. Therapy aims to
improve symptoms and prevent complications such as progressive heart failure, sudden death,
and thromboembolism.
The diagnosis of DCM is based on functional and morphological cardiac abnormalities.12 The
etiology of the underlying disorders is diverse in origin and mechanism, and includes genetic,
infectious, autoimmune and toxic causes.1,13,14 In around 50% of DCM cases no causal mechanism can be identified (idiopathic DCM). The contribution of familial forms of idiopathic
DCM is thought to be substantial: up to 35% of individuals with DCM have familial disease
(i.e. at least one other first-degree relative is affected).15,16 A further 20% of family members
have isolated LV enlargement with preserved systolic function, 10% of whom subsequently
develop overt DCM.17,18 In the majority of familial cases, DCM is transmitted as an autosomal
dominant trait, but other forms of inheritance are also recognized. Identifying family members
at risk and offering them periodic cardiological screening is advisable. This enables timely diagnosis to be made, with the possibility of preventing complications and reducing morbidity and
mortality. However, at present, our knowledge on prevention of disease in asymptomatic family
members at risk is limited. Outside of familial/genetic DCM, numerous causes of non-familial/
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Chapter 1
non-genetic DCM have been recognized (e.g. myocarditis, drug-related cardiomyopathy, and
peripartum cardiomyopathy).13,14
Currently, over 50 different genes have been associated with familial/genetic DCM (Figure 1),
and the list is still growing.19 Genes implicated in isolated DCM include genes encoding proteins
of the sarcomere and Z-disk (which have an important role in mechanosensation for the sarcomere). Other genes include those encoding proteins related to calcium or potassium channels, the nuclear envelope, heat-shock chaperones, and mitochondria.11 The mutation detection
rate for most DCM-related genes is low and, until recently, a causative mutation could be identified in less than a third of familial DCM cases. The identification of TTN as a major genetic
contributor to DCM increased this fraction to around 50%.20
Next-generation Sequencing
A dramatic advance in sequencing technology, called next-generation sequencing, recently
brought the efficiency of the assay from sequencing 1 gene over months to around 50 genes
overnight. This dramatically lowered the cost and the turnaround time, and increased the
sensitivity of genetic testing in disorders such as DCM.21,22 Moreover, next-generation sequencing
of the whole exome, which is the portion of the genome coding for all proteins of the human
body, has already produced important results in the study of DCM where the causal gene was
unknown.23,24 However, next-generation sequencing generates new challenges for geneticists
and clinicians: it is of utmost importance that identified sequence variants are appropriately
classified (benign, pathogenic, or of uncertain significance).25 With non-targeted approaches,
like whole exome (or eventually whole genome) sequencing, one should also be aware that
there is a chance of detecting unsolicited findings.
Founder Mutations
In the Netherlands, several founder mutations underlying different types of cardiomyopathies
have been identified.26-29 Founder mutations are mutations that emerged in a population many
generations ago and that have subsequently spread among following generations. Acknowledging the existence of founder mutations that cause cardiomyopathies is important for genetic
research and patient care. The fact that patients carrying founder mutations also share neighboring genetic regions (called haplotypes) helps us to identify the gene involved. Next, the
significant number of patients carrying founder mutations enables us to perform studies
focusing on genotype-phenotype relations and the subsequent elucidation of modifying factors
underlying the clinical variability.
Modifiers of Genetic/Familial Dilated Cardiomyopathy
The majority of DCM-related mutations cause disease with an incomplete and age-dependent
penetrance, as well as variable expression. This suggests a contribution of other genetic or
epigenetic and environmental factors, also called modifiers. The influence of these genetic or
epigenetic and environmental factors on the clinical expression of genetic DCM is an attractive research area. An interaction between several triggers that could lead to DCM (e.g. genetic,
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Figure 1: Genetic heterogeneity and overlap in genes causing cardiomyopathies.
This figure shows the genes underlying hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy
(DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), restrictive cardiomyopathy (RCM) and
non-compaction cardiomyopathy (LVNC). Adapted with modifications from Van Spaendonck et al.4 and
Jongbloed et al.5
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Chapter 1
infectious, toxic, pregnancy-related) may be present in a subset of cases.
Some observations underscore the principle that environmental variables can influence disease
expression in a primary genetic cardiomyopathy. For example, obesity and systemic hypertension can modify the HCM phenotype,30 and exercise increases penetrance and arrhythmogenic
risk in ARVC.31 But the role of genetic-environmental interactions in DCM has not been formally studied yet. In reverse, less penetrant genetic factors may modify the effect of environmental causes for DCM, for example, genetic modifiers in patients with myocarditis or drugrelated cardiomyopathy, or alcoholic cardiomyopathy.
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OUTLINE OF THIS THESIS
Inherited cardiomyopathies are clinically and genetically highly heterogeneous, especially
dilated cardiomyopathy (DCM). More than 50 DCM-related genes have been identified since
the 1990s. The majority of these genes only account for a minority of cases, and many mutations are unique to one family. At present, a genetic cause is found in around 50% of DCM
cases. Identifying the causative mutation can confirm a known or suspected diagnosis and
provides insight into the etiology of disease. Sometimes, the genotype can influence patient
care. However, for most DCM-related genes information about genotype-phenotype associations remains sparse. Identifying a causative mutation in an index patient facilitates genetic
cascade screening in family members, which can be helpful in identifying individuals at risk
(and in dismissing relatives who do not carry the mutation from regular cardiac monitoring).
This enables timely diagnosis to be made, with the possibility of preventing complications and
reducing morbidity and mortality. Genotype information can also be used for counseling of
mutation carriers regarding lifestyle, considering risk estimates for offspring and reproductive
options, and regarding the possible deterioration of DCM by environmental factors like pregnancy or drugs. However, the influence of environmental factors has not yet been completely
established.
This thesis presents genetic causes, phenotypic characterization, and gene-environment interactions in inherited cardiomyopathies, mainly DCM. Knowledge about these features is important for development of patient-specific treatment and/or management and genetic cascade
screening.
The first part of this thesis describes genetic causes and phenotypic characterization of inherited
cardiomyopathies, mainly DCM, with associated neuromuscular disease in a subset of cases.
The presence of founder mutations is an important feature of this section.
Chapter 2 presents an overview of 10 years’ experience with genetic analysis in index patients
with idiopathic DCM. The influence of characteristics in a patients’ medical and family history
on the yield of genetic analysis is studied. The clinical characteristics and outcome of the two
most prevalent mutated genes (LMNA and PLN) are presented. The high mutation detection
rate of PLN is due to a recently identified Dutch founder mutation. Chapters 3 and 4 are
about desmin-related myopathy, an inherited skeletal and cardiac myopathy mainly caused by
DES mutations. Chapter 3 describes a meta-analysis of all reported DES mutation carriers
and Chapter 4 describes the cardiac phenotype of two Dutch founder mutations in the DES
gene. Chapter 5 describes the discovery of the genetic cause of infantile type I muscle fiber
disease and cardiomyopathy, including a Dutch founder mutation in MYL2.
The second part of this thesis presents two hitherto unknown gene-environment interactions
in inherited cardiomyopathies: pregnancy and chemotherapy.
Chapter 6 shows a systematic study on the relation between peripartum cardiomyopathy (PPCM)
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Chapter 1
and familial DCM that strongly suggests that a subset of PPCM is an initial manifestation of
familial DCM. Chapter 7 presents the yield from targeted next-generation sequencing in families
with both PPCM and DCM. Chapter 8 is a review of the available literature about pregnancy
in women with inherited cardiomyopathies, emphasizing the importance of preconception
evaluation and genetic counseling. Chapters 9 and 10 describe examples and the first systematic
study on the concept that a genetic/familial predisposition for DCM can be a risk factor for
anthracycline-associated cardiomyopathy (AACM).
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