university of groningen inherited cardiomyopathies ... › research › portal › files › 2332861...

University of Groningen

Inherited CardiomyopathiesSpaendonck-Zwarts, Karin Yvon van

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Citation for published version (APA):Spaendonck-Zwarts, K. Y. V. (2014). Inherited Cardiomyopathies: Genetics and Gene-EnvironmentInteractions. Groningen: s.n.

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General introduction and outline of this thesis

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Spaendonck.indd 9 21-01-14 09:00

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Chapter 1

GENERAL INTRODUCTION

Inherited CardiomyopathiesCardiomyopathies are defined as myocardial disorders in which the heart is structurally and functionally abnormal in the absence of coronary artery disease, valvular heart disease, hyper-tension, 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 cardiomyo-pathy (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 domi-nant, 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 pro-portion 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 cardiomyopa-thies 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. Identifi-cation 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 clini-cal 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 rela-tives, in order to help individuals deal with the psychological, social, professional, ethical, and legal implications of a genetic disease.10

Dilated CardiomyopathyDilated cardiomyopathy (DCM) is defined as a myocardial disorder characterized by the pre-sence 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 pres-sure and/or low cardiac output (“heart failure”), whilst sudden cardiac death or a thromboem-bolic 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 mecha-nism 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 diag-nosis 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 sar-comere). Other genes include those encoding proteins related to calcium or potassium chan-nels, 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 iden-tified 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 SequencingA 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 MutationsIn 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. Acknow-ledging 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 neigh-boring 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 CardiomyopathyThe 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 attrac-tive 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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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 hyperten-sion 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 for-mally studied yet. In reverse, less penetrant genetic factors may modify the effect of environ-mental causes for DCM, for example, genetic modifiers in patients with myocarditis or drug-related 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 muta-tions 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 associa-tions 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 preg-nancy or drugs. However, the influence of environmental factors has not yet been completely established.

This thesis presents genetic causes, phenotypic characterization, and gene-environment interac-tions in inherited cardiomyopathies, mainly DCM. Knowledge about these features is impor-tant 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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2. Lekanne Deprez RH, Muurling-Vlietman JJ, Hruda J, Baars MJ, Wijmaendts LC, Stolte-Dijkstra I, Alders M, van Hagen JM. Two cases of severe neonatal hypertrophic cardiomyopathy caused by compound heterozygous mutations in the MYBPC3 gene. J Med Genet 2006;43:829-832.

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24. Norton N, Li D, Rieder MJ, Siegfried JD, Rampersaud E, Züchner S, Mangos S, Gonzalez-Quintana J, Wang L, McGee S, Reiser J, Martin E, Nickerson DA, Hershberger RE. Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy. Am J Hum Genet 2011;88:273-282.

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26. Alders M, Jongbloed R, Deelen W et al. The 2373insG muation in the MYBPC3 gene is a found-er mutation, which accounts for nearly one-fourth of the HCM cases in the Netherlands. Eur Heart J 2003;24:1848-1853.


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27. Van Tintelen JP, Entius MM, Bhuiyan ZA, Jongbloed R, Wiesfeld AC, Wilde AA, van der Smagt J, Boven LG, Mannens MM, van Langen IM, Hofstra RM, Otterspoor LC, Doevendans PA, Rodriguez LM, van Gelder IC, Hauer RN. Plakophilin-2 mutations are the major determinant of familial arrhthmogenic right ventricular dysplasia/cardiomyopathy. Circulation 2006;113:1650-1658.

28. van Tintelen JP, van Gelder IC, Asimaki A, Suurmeijer AJ, Wiesfeld AC, Jongbloed JD, van den Wijngaard A, Kuks JB, van Spaendonck-Zwarts KY, Notermans N, Boven L, van den Heuvel F, Veentsra-Knol HE, Saffitz JE, Hofstra RM, van den Berg MP. Severe cardiac phenotype with right ventricular predominance in a large cohort of patients with a single missense mutation in the DES gene. Heart Rhythm 2009;6:1574-1583.

29. Van der Zwaag PA, Rijsingen IA, Asimaki A, Jongbloed JD, van Veldhuisen DJ, Wiesfeld AC, Cox MG, van Lochem LT, de Boer RA, Hoftra RM, Christiaans I, van Spaendonck-Zwarts KY, Lekanne Dit Deprez RH, Judge DP, Calkins H, Suurmeijer AJ, Hauer RN, Saffitz JE, Wilde AA, van den Berg MP, van Tintelen JP. Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept op arrhythmogenic cardiomyopathy. Eur J Heart Fail 2012;14:1199-1207.

30. Olivotto I, Maron BJ, Tomberli B, Appelbaum E, Salton C, Haas TS, Gibson M, Nistri S, Servet-tini E, Chan RH, Udelson JE, Lesser JR, Cecchi F, Manning WJ, Maron MS. Obesity and its association to phenotype and clinical course in hypertrophic cardiomyopathy. J Am Coll Cardiol 2013;62:449-457.

31. James CA, Bhonsale A, Tichnell C, Murray B, Russell SD, Tandri H, Tedford RJ, Judge DP, Calkins H. Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic ven-tricular dysplasia/cardiomyopathy associated desmosomal mutation carriers. J Am Coll Cardiol 2013;62:1290-1297.


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