Sarcomeric genes that cause HCM
1. Introduction
Cardiomyopathies can be defined as disorders of the myocardium which are associated with cardiac dysfunction and are aggravated by arrhythmias, heart failure and sudden death [Ricardson, 2006]. Genetics has played a very important role in the understanding of the different cardiomyopathies since, in 1957, Bridgen cited for the first time the word “cardiomyopathy” and in 1958, Teare, the British pathologist reported nine cases of septum hypertrophy (Teare, 1958).
The American Heart Association (AHA) has classified cardiomyopathies as primary cardiomyopathies (the heart is the only organ affected) and secondary cardiomyopathies (the heart is affected as part of a systemic disease). The European Society of Cardiology (ESC) has classified them according to morphological and functional phenotypes involving their pathophysiology (Maron, 2006; Maron, 2008; Elliott, 2008)
Primary cardiomyopathies are those which and can be genetic, nongenetic or acquired. Secondary cardiomyopathies are those in which the cardiomyopathy is found in a systemic disease. Primary cardiomyopathies can then be classified according to their anatomical and functional impairment in hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM), arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), ion channel disorders. Secondary cardiomyopathies are those found in muscular dystrophies, mitochondrial disorders among others. The unclassified cardiomyopathies are non-compaction cardiomyopathy and takotsubo cardiomyopathy (Elliott, 2008; )
The genetic diagnosis has a close involvement in the management of primary and secondary cardiomyopathies and its development will have a key role in the understanding of the different molecular mechanisms that lead to a cardiomyopathy.
2. Hypertrophic cardiomyopathy
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, 2003, Richard, 2006).
As the prevalence of HCM is 1: 500, it can be stated that HCM is undoubtedly the most common cardiovascular disorder (Maron, 2002).
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 left ventricular hypertrophy (LVH) is usually asymmetric and involves the septum.
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 in young athletes while practicing sports.
HCM generally has normal systolic function, impaired diastolic function and outflow obstruction in about 25%. The histopathology shows myocyte disarray, interstitial fibrosis and hypertrophy (Richard, 2006, Ho, 2007).
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 (Richard, 2006 Hayashi, 2004; Frank, 2011).
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Beta-myosin heavy chain | CMH1 | 14q2 | Myosin heavy chain, cardiac muscle beta isoform | |
Myosin-binding protein C |
CMH4 | 11p11.2 | Myosin-binding protein C, cardiac-type | |
Troponin T | CMH2 | 1q32 | TroponinT, cardiac muscle | |
Troponin I | CMH7 | 19q13.4 | TroponinI, cardiac muscle | |
Alpha-tropomyosin | CMH3 | 15q22.1 | Tropomyosin1 alpha chain | |
Regulatory myosin light chain | CMH10 | 12q24.3 | Myosin regulatory light chain 2, ventricular/cardiac muscle isoform | |
Essential myosin light chain |
CMH8 | 3p21 5 | Myosin light polypeptide 3 | |
Actin | CMH11 | 15q14 | Actin, alpha cardiac muscle 1 | |
Cardiac troponin C | CMH13 | 3p21.1 | Troponin C, slow skeletal and cardiac muscles | |
Titin | CMH9 | 2q24.3 2 | Titin | |
Alpha-myosin heavy chain |
CMH14 | 14q12 | Myosin heavy chain, cardiac muscle alpha isoform | |
Muscle LIM protein |
CMH12 | 11p15. | Cysteine and glycine-rich protein 3, muscle LIM protein | |
Telethonin | CMH11 | 17q12 1 | Telethonin |
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.
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 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).
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Lamin A/C gene |
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CMD1A | 1q21 | lamin A and lamin C | AD |
LDB3 gene | CMD1C | 10q22-q23 | LIM domain-binding protein 3 | AD | |
TNNT2 gene | CMD1D | 1q32 | Troponin T, cardiac muscle | AD | |
SCN5A | CMD1E | 3p | Sodium channel protein type 5 subunit alpha | AD | |
TTN gene | CMD1G | 2q31 | Titin | AD | |
DES gene | CMD1I | 2q35 | Desmin | AD | |
EYA4 gene | CMD1J | 6q23-q24 | Eyes absent homolog 4 | AD | |
SGCD gene | CMD1L | 5q33 | Delta-sarcoglycan | AD | |
CSRP3 gene | CMD1M | 11p15.1 | Cysteine and glycine-rich protein 3 | AD | |
TCAP gene | CMD1N | 17q12; | Telethonin | AD | |
ABCC9 gene | CMD1O, | on 12p12.1; | ATP-binding cassette, subfamily C, member 9 | AD | |
PLN gene | CMD1P | on 6q22.1;, | Cardiac phospholamban | AD | |
ACTC1 gene | CMD1R | 15q14 | Actin, alpha cardiac muscle 1 | AD | |
MYH7 gene | CMD1S | 14q12; | Myosin 7 | AD | |
TMPO gene | CMD1T | 12q22 | Hymopoietin | AD | |
PSEN1 gene | CMD1U | 14q24.3 | Presenilin-1 | AD | |
PSEN2 gene | CMD1V | 1q31-q42; | Presenilin-2 | AD | |
metavinculin VCL | CMD1W | 10q22-q23 | metavinculin VCL | AD | |
fukutin | CMD1X | 9q31 | Fukutin | AD | |
TPM1 gene | CMD1Y | 15q22.1 | tropomyosin-1 | AD | |
TNNC1 gene | CMD1Z | 3p21.3-p14.3 | slow troponin-C | AD | |
ACTN2 gene | CMD1AA | 1q42-q43; | Alpha-actinin-2 | AD | |
DSG2 gene | CMD1BB | 18q12.1-q12.2; | desmoglein-2 | AD | |
NEXN gene | CMD1CC | 1p31.1 | Nelin | AD | |
RBM20 gene | CMD1DD | 10q25.2; | RNA-Binding motif protein 20 | AD | |
MYH6 gene | CMD1EE | 14q12 | Myosin 7 | AD | |
TNNI3 gene | CMD1FF | 19q13.4; | Troponin I, | AD | |
SDHA gene | CMD1GG | 5p15; | Succinate dehydrogenase complex subunit A | AD | |
BAG3 gene | CMD1HH | 10q25.2-q26.2 | BCL2-associated athanogene 3 | AD | |
TNNI3 gene | CMD2A, | 19q13.42 | Troponin I, cardiac muscle | AR | |
GATAD1 gene. | CMD2 |
7q21.2 | GATA zinc finger domain containing protein 1 | AR | |
Dystrophin gene |
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CMD3B | Xp21.2 | dystrophin | X-linked |
LAMP2 gene |
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Danon disease | Xq24 | lysosome-associated membrane protein-2 | X-linked |
TAZ gene |
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Xq28 | dystrophin | X-linked |
Mutations on the following genes
4. Restrictive cardiomyopathy
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 a grave prognosis (Kaski, 2008.)
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 (Kushwaha, 1997).
The familial RCM is linked to the cardiac troponin genes. RCM1 is caused by a mutation in the
In many cases RCM can be observed overlapping with either HCM or DCM. (Kamisago, 2000; Olson, 2002; Zang, 2005; Kaski, 2008).
5. Arrhythmogenic right ventricular cardiomyopathy / dysplasia
Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/ARVD) is a commonly inherited disorder with a family history in 30 to 50% of the cases (Klauke, 2010).
The prevalence has been estimated 1:2000 to 1:5000 in the general population (Peters 2006, Cox&Hauer, 2011).
ARVC is characterized by fibro-fatty replacement of the myocardium with a marked involvement of the right ventricle. ARVC can be defined by the presence either sectored or global right ventricular dysfunction. The left ventricular abnormalities which lead to DCM may take place later. Clinical features include tachyarrhythmias, electrocardiographic abnormalities, systolic heart failure, syncope and sudden death. ARVC is a frequent cause of sudden death in young people and athletes (Maron, 2006).
It is transmitted with an autosomal dominant pattern, though autosomal recessive families have also been reported. Incomplete penetrance and great variability in the symptoms have been observed (Hamid, 2002; Awad, 2008; Eliott, 2008; Klauke, 2010, Cox&Hauer, 2011).
Desmosomes are intercellular junctions that link intermediate filaments to the plasma membrane and are essential to tissues that experience mechanical stress such as the myocardium. Mutations in the cardiac desmosome genes are to be held responsible for most of the cases that cause the disorder. (See Table 3)
The mutations p.S13F, p.E114del and p.N116S in the desmin gene have the same ARVC cardiac phenotype. In transfection cells aggresome formation in the cytoplasm was observed (Van Titelen, 2007; Vernengo, 2010; Klauke, 2010). Only recently has it been proven that seven members of the Swedish family with ARVC7 had the p.Pro419Ser mutation in
Naxos disease and Carvajal disease are ARVC inherited in an autosomal recessive pattern. The former is caused by mutations in the plakoglobin gene on chromosome 17q21,2 and the latter by mutations in the desmoplakin gene on chromosome 6p24 (Protonotarios, 1986; McKoy, 2000; Schonberger, 2001; Cox&Hauer, 2011).
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Transforming growth factor beta- 3 |
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ARVD1 | 14q2 | Transforming growth factor beta-3 |
Ryanodine receptor 2 | ARVD2 | 1q43 | RYR2 | |
Unknown | Unknown | ARVD3 | 14q12-q22 | Unknown |
Unknown | Unknown | ARVD4 | 2q32 .1-q32.3 | Unknown |
transmembrane protein 43 |
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ARVD5 | 3p25 .1 | Transmembrane protein 43 |
Unknown | Unknown | ARVD6 | 10p14-p12 | Unknownn |
Desmin |
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ARVD7 | 2q35 | Desmin |
Desmoplakin |
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ARVD8 | 6p24 .3 | Desmoplakin |
Plakophilin-2 |
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ARVD9 | 12p11 .21 | Plakophilin-2 |
Desmoglein-2 |
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ARVD10 | 18q12 .1 | Desmoglein-2 |
Desmocollin-2 |
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ARVD11 | 18q12 .1 | Desmocollin-2 |
Junction plakoglobin |
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ARVD12 | 17q21 .2 | Junction plakoglobin |
Desmin |
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ARVC | 2q35 | Desmin |
6. Non–compaction cardiomyopathy
Non-compaction cardiomyopathy (NCCM) has been classified as a primary cardiomyopathy with a genetic etiology.The age of onset varies from neonatal to adult hood. There is variability in the clinical features which include heart failure, arrhythmias and thromboembolism, but patients can also be asymptomatic]. The most common congenital heart defects in NCCM are Ebstein’s anomaly, septal defects and patent ductus arteriosus,
The patients have a thickened two-layered myocardium with a thin, compact, epicardial layer and a severely thickened endocardial layer with a ‘spongy’ appearance due to prominent trabeculations and intertrabecular recesses (Hermida-Prieto, 2004; Freedom, 2005; Budde, 2007; Monserrat, 2007; Klaassen, 2008)
The majority of the patients have an autosomal dominant mode of inheritance.
Mutations in several genes coding for sarcomeric proteins have been described in NCCM, such as β-myosin heavy chain (
7. Takotsubo cardiomyopathy
Takotsubo cardiomyopathy is characterized by an acute but transitient LV systolic dysfunction without atherosclerotic coronary artery disease and it is triggered by psychological stress (Sharkey, 2005; Sealove, 2008).
8. Ion channel disorders
The cell membrane transit of sodium and potassium ions is ruled by the ion channel genes which encode proteins responsible for the right transit of these ions. Mutations in these proteins lead to a group of familial disorders (Aleong, 2007). These ion channel disorders include the Romano-Ward syndrome (long QT syndromes), the short-QT syndrome (SQTS), Brugada syndrome, and the catecholaminergic polymorphic ventricular tachycardia (CPVT). 5% to 10% of the sudden deaths in children can be associated to ion channel disorders (Modell & Lehmann, 2006).
The clinical diagnosis of the ion channelopathies can be often made by identification of alterations found on the ECG (Aleong, 2007; Kass, 2005).
8.1. Romano–Ward syndrome
RWS may be sporadic or transmitted as an autosomal-dominant trait with reduced penetrance. It is the most common form of inherited long QT syndrome. The prevalence of RWS has been estimated to be 1:3000 to 1:7000.
The Romano-Ward syndrome (RWS) is tipically identified in patients that present syncope, seizures, or sudden death due to episodic taquiarrhythmias, QT prolongation and T-wave abnormalities, interval torsade de pointes that lead to ventricular fibrillation and death.
RWS is associated with mutations in the following genes:
8.2. Jervell and Lange–Nielsen syndrome
The Jervell and Lange-Nielsen syndrome (JLNS) is inherited as an autosomal recessive trait. The affected children present symptoms before the age of three and they died before the age of 15 if they are not treated.
The prevalence can vary considerably and it depends on the population studied.
The patients have a more severe QT prolongation (greater than 500 msec) which is associated which tachiarrhythmias including torsade de pointes, ventricular fibrillation, syncope and sudden death.
Mutations in the
8.3. Timothy syndrome
Timothy syndrome is a rare autosomal dominant disorder are due to either a
This complex multisystem disorder has a long QT syndrome associated with syndactily. Various forms of congenital heart defects such as tetralogy of Fallot, hypertrophic cardiomyopathy have been observed. The type 2 patients that have been reported did not have syndactily (Splawski, 2005)
Children died at age of 2.5 years due to ventricular tachycardia and ventricular fibrillation, infection or hypoglycemia (Reichenbach, 1992; Marks, 1995a; Marks 1995b; Splawski 2004; Lo-A-Njoe, 2005).
8.4. Brugada syndrome
The Brugada syndrome, which is inherited in an autosomal dominant pattern, is associated with sudden death in young people as the patients have malignant ventricular tachyarrhythmias and sudden cardiac death. The heart is not affected by either a structural heart or systemic disease.
The age of appearance ranges from a two- day- old patient to 85 years (Marks, 1995a; Marks, 1995b; Splawski, 2004; Huang, 2004; Lo-A-Njoe, 2005).
The cardiac differential diagnosis must be made with Duchenne muscular dystrophy, Friedreich ataxia and ARVC.
8.5. Catecholaminergic polymorphic ventricular tachycardia
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited tachyarrhythmia that is caused by acute adrenergic activation during exercise or acute emotion in young adolescents.
The age of onset varies from 7-9 years to the fourth decade of life.
It presents locus heterogeneity and in only approximatedly 50% of the cases the mutations in the genes causing the disease have been identified.
The prevalence of CPVT in the population is not known, but it could be estimated in approximately 1:10,000.
There is an autosomal dominant form caused by mutations in the RYR2 gene that encodes the ryanodine receptor 2, a calcium-release channel (George, 2003).
The autosomal recessive form is due to mutations in the calsequestrin 2 gene on chromosome 1p13.1 (Wilde, 2008).
8.6. Short–QT syndrome
Short-QT syndrome is a familial disease that is characterized by a high incidence of sudden death. Patients with this disease have QT intervals that are <300 ms, and increased risk of atrial and ventricular arrhythmia.
It is an autosomal dominant inherited disorder that affects patients of 30 years of age, but the fibrillation can even be observed in newborns and young patients.
Missense mutations in the
9. Cardiomyopathy in muscular dystrophies
Muscular dystrophies are a heterogeneous group of inherited disorders, characterized by progressive weakness and wasting of the skeletal muscles. They are generally associated with cardiomyopathy. In many cases, there is no correlation between the skeletal myopathy and the involvement of the heart. The mutations of the genes that cause muscular dystrophies affect the skeletal and/or cardiac muscles. These include proteins which are associated with the dystrophin–glycoprotein complex, the nuclear lamina or the sarcomere (Hermans, 2012).
Cardiomyopathy occurs in myofibrillar myopathy, myotonic dystrophies, myotonic myopathies, dystrophinopathies, Emery-Dreifuss muscular dystrophy, and limb girdle muscular dystrophies (Hermans, 2012).
They are inherited in autosomal dominant, autosomal recessive and X-linked mode. (See Table 4, Table 5).
The different forms of muscular dystrophies vary in the age of onset with no male or female prevalence and have different clinical features and severity. Mutations in the genes that are involved muscular dystrophies can cause hypertrophic, dilated or restrictive cardiomyopathy, but most cardiomyopathies in patients with a muscular dystrophy are of the dilated type. The progression of the disorders and life expectancy vary widely, even among different members of the same family. Patients die of sudden death due to conduction defects, and heart failure.
In dystrophinopathies, sarcoglycanopathies, and the disorders that are linked to mutations in the fukutin-related protein, the feature that stands out is the cardiomyopathy the patients suffer. In muscular dystrophies, the patients usually have a dilated cardiomyopathy. Hypertrophic cardiomyopathy can be observed in Danon disease, α-B crystallinopathy, and on patients or carriers of DMD and BMD. (De Ambroggi, 1995, Vicart 1998; Nguyen, 1998; Lazarus, 1999; Melacini, 1999; Barresi, 2000; Politano, 2001; Selcen, 2003; Fanin, 2001; Jefferies, 2005; Nakanishi, 2006; Connuck, 2008; Kaspar, 2009; Goldfarb, 2009; Lilienbaum, 2012; Hermans, 2012)
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Desminopathy | Desmin |
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MFM1 |
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Desmin | AD/AR |
Alpha-B crystallinopathy | CRYAB gene |
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MFM2 | 11q23.1 | alpha-B-crystallin | AR/AD |
Myotilinopathy | Myotilin | MFM3 | 5q31.2 | Myotilin (titinmmunoglobulin domain protein) |
AD | |
ZASPopathy | ZASP |
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MFM4 |
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LIM domain-binding protein 3 | AD |
Filaminopathy | FilaminC |
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MFM5 | 7q32.1 | Filamin C | AD |
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BCL2-associated athanogen 3 |
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BAG3 |
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BAG family molecular chaperone regulator 3 | AD |
Myotonic dystrophy type 1 | myotonin-protein kinase (Mt-PK). |
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DMPK | 19q13.3 | dystrophia myotonica-protein kinase | AD |
Myotonic dystrophy type 2 | zinc finger protein-9 gene |
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zinc finger protein-9 | AD | |
Duchenne/Becker muscular dystrophy | dystrophin |
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DMD | Xp21.2 | dystrophin | X-linked |
Emery-Dreyfuss Muscular Dystrophy1,X-linked | EMD gene |
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EMD1 | Xq28 | emerin | X-linked |
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LGMD2C | gamma sarcoglycan gene |
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SGCG | 13q12-q13 | gamma sarcoglycan | AR |
LGMD2D | alpha sarcoglycan gene |
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SGCA | 17q21 | Alpha sarcoglycan | AR |
LGMD2E | Beta sarcoglycan gene |
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SGCB | 4q12 | Beta sarcoglycan | AR |
LGMD2F | Delta sarcoglycan gene |
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SGCD | 5q33-q34 | Delta sarcoglycan | AR |
LGMD2I | fukutin related protein gene |
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FKRP | 19q13.32 | fukutin related protein | AR |
10. Mitochondrial disorders
Mitochondrial disorders are a heterogeneous group of disorders that have common clinical features and are caused by the different mutations found in either the nuclear or mitochondrial DNA (mtDNA) genes which regulate the mitochondrial respiratory chain, the essential final common pathway of aerobic metabolism, tissues and organs. mtDNA is maternally inherited and the disorders can appear at any age. All the mitochondria have multiple copies of their own mtDNA and the mutation rate is much higher than in nuclear DNA (Walter, 2000; Carrasco, 2005; De Jonge, 2011).
Many mitochondrial disorders involve multiple organ systems such as the brain, the heart, the liver, and the skeletal muscles which are, therefore, affected due to the fact they depend on the energy and they are especially susceptible to energy metabolism impairment (Walter, 2000; Carrasco, 2005; De Jonge, 2011).
Mitochondrial dysfunction and clinical symptoms appear when the heteroplasmic levels are above 80%-90% (Walter, 2000; Carrasco, 2005; De Jonge, 2011).
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 cardiomyopathies have been reported (Holmgren, 2003, de Jonge, 2011).
11. Kearns-Sayre syndrome
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 cerebrospinal fluid protein concentration greater than 100 mg/d, and a commonly elevated lactate and pyruvate concentrations in blood and cerebrospinal fluid are found.
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 usually dilated (Roberts, 1979; Anan, 1995; Carrasco, 2005).
11.1. MELAS
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 inheritance.
The cardiac involvement is considered to be 18–100% (Hirano, 1994; Vydt, 2007; Wortmann, 2007). The first symptom the affected children have is the cardiomyopathy. The most common feature is a hypertrophic cardiomyopathy, although dilation has also been reported (Okajima, 1998).
Mutations in the nuclear genes that also encode mitochondrial proteins can cause cardiomyopathies. These disorders are sometimes not considered among the group of mitochondrial primary disorders. Two of the most well known disorders are Friedreich´s ataxia and Barth syndrome (de Jonge, 2011).
Friedreich´s ataxia is an autosomal recessive disorder. Frataxin, the protein encoded by
Barth syndrome is a recessive X-linked inherited disease chacterized by cardiomyopathy and neutropenia. The cardiac disease presents a dilated cardiomyopathy, often with a degree of left myocardial thickening and, sometimes, endocardial fibroelastosis. The cardiac disease appears at birth or in the first few months of life
Mutations in the tafazzin gene are to be held responsible for this disorder because of the inhibition of this pathway leads to changes in mitochondrial architecture and function (Spencer, 2006, Schamme, 2006).
12. The impact of genetics in the understanding of cardiomyopathy
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).
In some cases, patients have two different mutations, usually in
The genotype-phenotype correlations have been linked to specific mutations (Richard, 2006).
The different mutations in the
All the patients that have mutations in the
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
All affected members of a RCM-associated family have the I79N mutation in the
It is very difficult to assess the genotype-phenotype correlation in NCCM. It seems that when there are mutations in the alpha-dystrobrevin gene (
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
In Timothy syndrome the molecular diagnosis of
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
It has suggested that the mutations in the nuclear gene
Approximately 80% of cases of MELAS are due to mutations in the mtDNA gene
13. What should the genetic counseling be in cardiomyopathy?
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 that cause it, locus heterogeneity and clinical variability.
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 child because they have misinterpreted the information provided to them.
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 do not have an identified causing gene defect.
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 the molecular test of the disorder would be inappropriate. If a mutation is found, the children will not longer lead a normal life and it will also have a negative effect on family life.
In HCM, the first step the geneticist should take is to order the molecular analyses of
Should the mutations not be in these two genes, the genetic analyses of
Sometimes, if no mutations are found in any of the genes tested, the disorder cannot be ruled out because it is likely that a new gene not yet discovered can be the cause.
In DCM the mode of inheritance has to be defined in other to provide a correct counseling as the there is locus and allelic heterogeneity.
In the autosomal dominant cardiomyopathies most individuals diagnosed have an affected parent. However, the index case may have the disorder as the result of a
In HCM, it is not known the number of cases that are caused by these
Timothy syndrome is due to either a
Only the siblings are at risk of inheriting the disorder.
When there is a
The offspring of a patient suffering autosomal dominant familial cardiomyopathy has a 50% chance of inheriting the mutation. Families in which penetrance appears to be incomplete or reduced have been observed; therefore a parent with a mutation that causes the disorder is not affected whereas the son or daughter is. The severity and age of onset cannot be predicted.
The siblings of the index case depend on the genetic condition of their parents. If a parent is affected or has the mutation that causes the disorder, the risk to inherit the mutated allele is 50%.
In the cases reported where more than one mutation in one the genes encoding a sarcomere protein has been identified in a patient with HCM, it is very difficult to assess the mode of inheritance and makes it arduous for the geneticist to give an accurate risk assessment to another family member.
It is essential to provide patients and relatives that are at risk, the potential risk their offspring might have in these disorders and the reproductive options they have.
In the autosomal recessive traits the parents are obligate carriers. The offspring of a patient suffering an autosomal recessive familial cardiomyopathy will be obligate carriers. The siblings have a 25% chance of inheriting the mutation.
The deletions in mtDNA are usually due to
When there are multiple mtDNA deletions the analysis of
A prenatal diagnosis for those patients there are at risk for any cardiomyopathy is possible, if the mutation carried by the parents or the proband has been previously identified.
Preimplantation genetic diagnosis (PGD) may be available for families in which the mutation that causes the disorder has already been identified.
14. Conclusion
In spite of the fact that there has been considerable improvement in the molecular diagnosis of the different mutations that lead to cardiomyopathies, we still have to learn more about the pathophysiology of these sometimes deadly disorders.
References
- 1.
Aernout Somsen, Kees Hovingh G, Tulevski I. Familial dilated cardiomyopathy. In Baars H, van der Smagt, J, Doevendans P, editors. Clinical Cardiogenetics: Springer 2011; p. 63-78. - 2.
Aleong, R.G., Milan, D.J. & Ellinor, P.T. (2007). The diagnosis and treatment of cardiac ion channelopathies: congenital long QT syndrome and Brugada syndrome. Cur Treat Opt in Cardio Med 2007; 9; 5:364-371. - 3.
Al-Jassar C, Knowles T, Jeeves M et al. The nonlinear structure of the desmoplakin plakin domain and the effects of cardiomyopathy-linked mutations. J Mol Biol. 2011 411:1049-1061. - 4.
Annan R, Nakagawa M, Miyata M et al. Cardiac involvement in mitocondrial disease. A study of 17 patients with documental mitochondrial DNA defects. Circulation 1995; 91:955-961. - 5.
Awad M, Calkins H, Judge D. Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy.Nat Clin Pract Cardiovasc (2008);5:258-67 - 6.
Baig M, Goldman J, Caforio A et al. Familial dilated cardiomyopathy: cardiac abnormalities are common in asymptomatic relatives and may represent early disease. J Am Coll Cardiol 1998; 3:195–201. - 7.
Bahl A, Saikia U & Khullar Madhu. Idiopathic restrictive cardiomyopathy- perspectives from genetics studies. Is it time to Redefine these disorders. Cardiogenetics 2012: 2e4. - 8.
Barresi R, Di Blasi C, Negri T, et al. Disruption of heart sarcoglycan complex and severe cardiomyopathy caused by beta sarcoglycan mutations. J Med Genet 2000; 37:102–107. - 9.
Becane H, Bonne G, Varnous S et al. High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation. Pacing Clin Electrophysiol 2000; 23:1661–6. - 10.
Begoña B, Brugada J et al. The Brugada syndrome. In Baars H, van der Smagt, J, Doevendans P, editors. Clinical Cardiogenetics: Springer 2011; p.165-188. - 11.
Budde B, Binner P, Waldmuller S et al. Noncompaction of the ventricular myocardium is associated with a de novo mutation in the beta-myosin heavy chain gene. PLoS One.2007; 2:e1362. - 12.
Brodsky G, Muntoni F, Miocic S et al. Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement. Circulation 2000; 101:473–6. - 13.
Carrasco L, Vernengo L, Mesa R et al. Síndrome de Kearns-Sayre. Presentación de un caso clínico y revisión de la bibliografía. Arch. Inst. Neurol. 2005; 8(2):31-35. [Article in Spanish. Abstract in English]. - 14.
Christiaans I & Carrier L. Hypertrophic cardiomyopathy In Baars H, van der Smagt, J, Doevendans P, editors. Clinical Cardiogenetics: Springer 2011; p.47-61. - 15.
Connuck D, Sleeper L, Colan S et al. Characteristics and outcomes of cardiomyopathy in children with Duchenne or Becker muscular dystrophy: a comparative study from the Pediatric Cardiomyopathy Registry. Am Heart J 2008; 155:998–1005. - 16.
Cox M & Hauer R. Arrhythmogenic right ventricular dysplasia/ cardiomyopathy from desmosome to disease. In Baars H, van der Smagt, J, Doevendans P, editors. Clinical Cardiogenetics: Springer 2011; p 80-96. - 17.
Crilley J, Boehm E, Blair E et al. Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy. J Am Coll Cardiol 2003;41:1776–1787. - 18.
De Ambroggi L, Raisaro A, Marchiano V, Radice S, Meola G. Cardiac involvement in patients with myotonic dystrophy: characteristic features of magnetic resonance imaging. Eur Heart J 1995;16:1007–10. - 19.
Danek A, Rubio J, Rampoldi L et al. McLeod neuroacanthocytosis: genotype and phenotype. Ann Neurol 2001; 50:755–764. - 20.
De Jonge N & Kirkels J. Restrictive cardiomyopathy. In Baars H, van der Smagt, J, Doevendans P, editors. Clinical Cardiogenetics: Springer 2011; p.123-128. - 21.
Di Mauro S, Bonilla E, Zeviani M et al. Mitochondrial myopathies. Ann Neurol 1985; 17:521-538. - 22.
Dooijes D, Hoedemaekers Y, Michels M et al. Left ventricular noncompaction cardiomyopathy: disease genes, mutation spectrum and diagnostic implications. Submitted. 2009. - 23.
Elliott, P. Cardiomyopathy. Diagnosis and management of dilated cardiomyopathy. Heart 2000 84; 1; 106-112. - 24.
Elliott P, Andersson, B, Arbustini E et al. Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases. Euro Heart Journal 2008; 29:270-276. - 25.
Fanin M, Melacini P, Boito C et al. LGMD2E patients risk developing dilated cardiomyopathy. Neuromuscul Disord 2003;13:303–309. - 26.
Frank D & Frey N. Cardiac Z-disc Signaling Network. JBC 2011 286; 12: 9897–9904 - 27.
Freedom, R, Yoo, S, Perrin D et al. The morphological spectrum of ventricular noncompaction. Cardiology in the Young 2005; 15:345-364. - 28.
Ga Overeem S, Schelhaas H, Blijham P et al. Symptomatic distal myopathy with cardiomyopathy due to a MYH7 mutation. Neuromuscul Disord 2007;17:490–3. - 29.
George C, Higgs G, Lai F. Ryanodine receptor mutations associated with stress-induced ventricular tachycardia mediate increased calcium release in stimulated cardiomyocytes. Circ Res. (2003); 93:531–534. - 30.
Goodwin JF.Cardiomyopathies and specific heart muscle diseases. Definitions, terminology, classifications and new and old approaches. Postgrad Med J. 1992;68 Suppl 1:S3-6. - 31.
Goldfarb L, Dalakas M. Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease. J Clin Invest 2009; 119:1806–1813. - 32.
Hamid M, Norman M, Quraishi A, et al. Prospective evaluation of relatives for familial arrhythmogenic right ventricular cardiomyopathy/dysplasia reveals a need to broaden diagnostic criteria. J Am Coll Cardiol. 2002;40:1445-1450. - 33.
Hayashi T, Arimura T, Itoh-Satoh M, et al. Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. J Am Coll Cardiol. 2004;44:2192-2201. - 34.
Hedberg C, Melberg A, Kuhl A et al. Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy 7 is caused by a DES mutation. Eur J Hum Genet 2012; 20:984-985. - 35.
Hermida-Prieto MML, Castro-Beiras A, Laredo R et al. Familial dilated cardiomyopathy and isolated left ventricular noncompaction associated with Lamin A/C gene mutations. Am J Cardiol. 2004; 94:50 –54. - 36.
Ho C, Lever H, DeSanctis R, Farver C et al. Homozygous mutation in cardiac troponin T: implications for hypertrophic cardiomyopathy. Circulation 2000;102:1950-1955. - 37.
Hoedemaekers Y, Caliskan K, Michels M. The importance of genetic counseling, DNA diagnostics and cardiologic family screening in left ventricular noncompaction cardiomyopathy. Circ Cardiovasc Genet. 2010; 3:232-239. - 38.
Hoedemaekers Y, Caliskan K, Majoor-Krakauer D. Non-compaction cardiomyopathy. In Baars H, van der Smagt, J, Doevendans P, editors. Clinical Cardiogenetics: Springer 2011; P.98-122. - 39.
Holgrem D, Wahlander H, Eriksson, B et al. Cardiomyopathy in children with mitochondrial disease: clinical course and cardiologigal findings. Eur Heart J 2003; 24:280-288.. - 40.
Ichida F, Tsubata S, Bowles KR et al. Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome. Circulation. 2001;103:1256 –1263. - 41.
Ingles J, Doolan A, Chiu C et al. Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling. J Med Genet. 2005;42:e59. - 42.
Jefferies, J & Towbin, J. (2010). Dilated cardiomyopathy. Lancet 2010; 375:752-762. - 43.
Jefferies J, Eidem B, Belmont J et al. Genetic predictors and remodeling of dilated cardiomyopathy in muscular dystrophy. Circulation 2005; 112:2799–804. - 44.
Kamisago M, Sharma S, DePalma S et al. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. New Eng. J. Med. 2000; 343: 1688-1696 - 45.
Kass, R.S. The channelopathies: novel insights into molecular and genetic mechanisms of human disease J Clin Invest 2005; 115: 1986-1989, - 46.
Katritsis D, Wilmshurst P, Wendon J et al. Primary restrictive cardiomyopathy: clinical and pathologic characteristics. J Am Coll Cardiol 1991;18:1230-1235 - 47.
Klaassen S, Probst S, Oechslin E et al. Thierfelder L. Mutations in sarcomere protein genes in left ventricular noncompaction. Circulation 2008; 117:2893–2901 - 48.
Kaski J, Syrris P, Burch M, Tomé-Esteban M et al. Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes. Heart 2008; 94:1478–1484. - 49.
Kaspar R, Allen H, Ray W et al. Alvarez CE, Kissel JT, Pestronk A, et al. Analysis of dystrophin deletion mutations predicts age of cardiomyopathy onset in Becker muscular dystrophy. Circ Cardiovasc Genet 2009; 2:544–51. - 50.
Kirkels J & de Jonge N.Mitochondrial cardiomyopathy. In Baars H, van der Smagt, J, Doevendans P, editors. Clinical Cardiogenetics: Springer 2011; p123-128. - 51.
Kirkels J & de Jonge N. Restrictive cardiomyopathy. In In Baars H, van der Smagt, J, Doevendans P, editors. Clinical Cardiogenetics: Springer 2011; p130-139. - 52.
Klauke B, Kossmann S, Gaertner A et al. De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy. Hum Mol Genet 2010; 19; 4595–4607. - 53.
Kumar Singh B, Kolappa Pilla K et al. Classification and definitions of cardiomyopathies. In Joseph Veselka, editor.: Cardiomyopathies –from basic research to clinical management InTech 2012; p.3-20. - 54.
Kushwaha S, Narula J, Narula N et al.Pattern of changes over time in myocardial blood flow and microvascular dilator capacity in patients with normally functioning cardiac allografts. Am J Cardiol. (1998); 82:1377-81. - 55.
Lazarus A, Varin J, Ounnoughene Z et al. Relationships among electrophysiological findings and clinical status, heart function, and extent of DNA mutation in myotonic dystrophy. Circulation 1999; 99:1041–6. - 56.
Lilienbaum A & Vernengo L. Cardiomyopathies associated with myofibrillar myopathies .In Joseph Veselka, editor.: Cardiomyopathies –from basic research to clinical management InTech 2012; p.353-382. - 57.
Lo-A-Njoe SM, Wilde AA et al. Syndactyly and long QT syndrome (CaV1.2 missense mutation G640R) is associated with hypertrophic cardiomyopathy. Heart Rhythm. 2005; 2:1365–1368. - 58.
Mangin L, Charron P, Tesson F et al. Familial dilated cardiomyopathy: clinical features in French families.. Eur J Heart Fail 1999; 1 4: 353-361. - 59.
Marian A, Roberts R. The molecular genetic basis for hypertrophic cardiomyopathy. J Mol Cell Cardiol 2001; 33:655. - 60.
Marks M, Trippel D, Keating M. Long QT syndrome associated with syndactyly identified in females. Am J Cardiol. 1995a;76:744–5. - 61.
Marks ML, Whisler SL, Clericuzio C, Keating M. A new form of long QT syndrome associated with syndactyly. J Am Coll Cardiol. 1995b; 25:59–64. - 62.
Maron, BJ. Cardiology patient pages. Hypertrophic cardiomyopathy. Circulation (2002); 106:2419-2421, - 63.
Maron BJ, Towbin JA, Thiene G et al.. Contemporary definitions and classification of the cardiomyopathies. An American Heart Association scientific statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation (2006). 1;113:1807–1816. - 64.
Maron, B.J. (2008). The 2006 American Heart Association classification of cardiomyopathies is the gold standard. Circulation Heart Failure (2008). 1; 72-75. - 65.
McKoy G, Protonotarios N, Crosby A et al. Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet. (2000); 355:2119-2124. - 66.
Melacini P, Fanin M, Duggan D et al. Heart involvement in muscular dystrophies due to sarcoglycan gene mutations. Muscle Nerve 1999; 22:473–479. - 67.
Melberg A, Oldfors, A, Blomstrom-Lundqvist C et al. Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy linked to chromosome 10q .Ann. Neurol. 46: 684-692, 1999. - 68.
Menon S., Michels V, Pellikka et al. Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology. Clin. Genet. 2008; 74: 445-454. - 69.
Mestroni L, Rocco C, Gregori D, et al. Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. Heart Muscle Disease Study Group. J Am Coll Cardiol 1999; 34:181–90. - 70.
Michels V, Moll P, Miller F et al. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N Engl J Med 1992; 326:77– 82. - 71.
Modell, S.M. & Lehmann, M.H. (2006).The long QT syndrome family of cardiac ion channelopathies: a HuGE review. . Genet in Med 2006; 8;143-155 - 72.
Moolman J, Corfield V, Posen B et al. Sudden death due to troponin T mutations. J Am Coll Cardiol 1997;29:549. - 73.
Monserrat L, Hermida-Prieto M, Fernandez X et al. Mutation in the alpha-cardiac actin gene associated with apical hypertrophic cardiomyopathy, left ventricular noncompaction, and septal defects. Eur Heart J. 2007; 28:1953–1961. - 74.
Nakanishi T, Sakauchi M, Kaneda Y et al. Cardiac involvement in Fukuyama-type congenital muscular dystrophy. Pediatrics 2006;117:e1187–119. - 75.
Nguyen H, Wolfe 3rd J, Holmes Jr D, Edwards W. Pathology of the cardiac conduction system in myotonic dystrophy: a study of 12 cases. J Am Coll Cardiol 1988; 11:662–71. - 76.
Nimura H, Bachinski L, Sangwatanaroj S et al. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med 1998;338:1248–57. - 77.
Nimura H, Patton K, McKenna W et al. Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation. 2002;105:446–51 - 78.
Norgett E, HatsellS, Carvajal-Huerta L et al. Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum. Mol. Genet 2000; 9:2761-2766. - 79.
Okajima Y, Tanabe Y, Takayanagi M, Aotsuka H. A follow up study of myocardial involvement in patients with mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS). Heart. (1998); 80:292-295. - 80.
Olson T; Illenberger S, Kishimoto N et al. Metavinculin mutations alter actin interaction in dilated cardiomyopathy. Circulation. 2002; 105: 431-437. - 81.
Peddy S, Vricella L, Crosson J et al. Infantile restrictive cardiomyopathy resulting from a mutation in the cardiac troponin T gene. Pediatrics 2006; 117:1830-1833. - 82.
Peters S. Advances in the diagnostic management of arrhythmogenic right ventricular dysplasia-cardiomyopathy. Int J Cardiol. 2006;113:4–11. - 83.
Politano L, Nigro V, Passamano L et al. Evaluation of cardiac and respiratory involvement in sarcoglycanopathies. Neuromuscul Disord 2001;11:178–185. - 84.
Protonotarios N, Tsatsopoulou A, Patsourakos P et al. Cardiac abnormalities in familial palmoplantar keratosis. Brit. Heart J. 56: 321-326, 1986. - 85.
Richard P, Isnard R, Carrier L, et al. Double heterozygosity for mutations in the beta-myosin heavy chain and in the cardiac myosin binding protein C genes in a family with hypertrophic cardiomyopathy. J Med Genet. 1999;36:542-545. - 86.
Richard P, Charron P, Carrier L, et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003;107:2227-2232. - 87.
Richard P, Villard E, Charron P, Isnard R. The genetic bases of cardiomyopathies. J Am Coll Cardiol. 2006;48:A79–8 - 88.
Richardson P, McKenna W, Bristow M, et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies. Circulation 1996;93:841–842. - 89.
Roberts N, Perloff J, Kark R. A follow up study of myocardial involvement in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Heart (1998);80:292-2955. - 90.
Sealove B, Tiyyagura S, & Fuster, V. Takotsubo cardiomyopathy. J of Gen Intern Med, 2008; 23; 1904-1908. - 91.
Schlame M, Ren M. Barth syndrome, a human disorder of cardiolipin metabolism. FEBS Lett. (2006) ;580:5450-5455. - 92.
Schonberger J, Seidman CE. Many roads lead to a broken heart: the genetics of dilated cardiomyopathy. Am. J. Hum. Genet. 69: 249-260, 2001. - 93.
Schoser B, Ricker, K, Schneider-Gold C et al. Sudden cardiac death in myotonic dystrophy type 2. Neurology 2004; 63: 2402-2404. - 94.
Schwartz P, Moss A, Vincent G, Crampton R. Diagnostic criteria for the long QT syndrome. An update. Circulation. (1993); 88:782–784. - 95.
Schwartz P, Priori S, Spazzolini C et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation. (2001);103:89–95. - 96.
Schwartz P, Crotti L. QTc behavior during exercise and genetic testing for the long-QT syndrome. Circulation. (2011); 124:2181–2184. - 97.
Selcen D, Engel AG. Myofibrillar myopathy caused by novel dominant negative alpha B-crystallin mutations. Ann Neurol 2003; 54:804–810. - 98.
Shan L, Makita N, Xing Y et al. SCN5A variants in Japanese patients with left ventricular noncompaction and arrhythmia. Mol Genet Metab. 2008;93:468–474. - 99.
Sharkey S., Lesser J, Zenovich et al.. Acute and reversible cardiomyopathy provoked by stress in women from the United States. Circulation 2005; 111:472-479 - 100.
Spencer C, Bryant R, Day J et al. Cardiac and clinical phenotype in Barth syndrome. Pediatrics 2006;118:e337–346. - 101.
Splawski I, Timothy K, Sharpe L et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell (2004); 119:19-31. - 102.
Splawski I, Timothy KW, Decher N et al. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci USA. (2005); 102:8089–8096. - 103.
Sugrue DD, Rodeheffer RJ, Codd MB, et al. The clinical course of idiopathic dilated cardiomyopathy: a population-based study. Ann Intern Med (1992);117:117–123. - 104.
Tardiff JC. Sarcomeric proteins and familial hypertrophic cardiomyopathy: linking mutations in structural proteins to complex cardiovascular phenotypes. Heart Fail Rev 2005;10:237 - 105.
Teare D.Asymmetrical hypertrophy of the heart Br heart J 1958;20:1-8 Postgrad Med J 1992;68 Suppl 1:S3-6. - 106.
Thierfelder, L., Watkins, H., MacRae, C et al .Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere, Cell 1994; 77: 701-712, - 107.
Uro-Coste E, Arne-Bes M, Pellissier J et al. Striking phenotypic variability in two familial cases of myosin storage myopathy with a MYH7 Leu1793pro mutation. Neuromuscul Disord 2009; 19:163–1636. - 108.
Van der Werf C & Wilde A. Catecholaminergic polymorphic ventricular tachycardia. In Baars H, van der Smagt, J, Doevendans P, editors. Clinical Cardiogenetics: Springer 2011; p.197-206. - 109.
Van der Zwaag, P, Jongbloed J, van den Berg M et al. A genetic variants database for arrhythmogenic right ventricular dysplasia/cardiomyopathy. Hum Mutat 2009; 30:1278–1283. - 110.
Van Driest SL, Vasile VC, Ommen SR, Will ML, Jamil Tajik A, Gersh BJ,Ackerman MJ. Myosin binding protein C mutations and compoundheterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol2004;44:1903–1016 ; - 111.
Van Tintelen J, Van Gelder I, Asimaki A et al. 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. - 112.
Vatta M, Mohapatra B, Jimenez S et al. Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular noncompaction. J Am Coll Cardiol 2003;42:2014 –2027. - 113.
Vernengo L, Choubargi O, Panuncio A et al. Desmin myopathy with severe cardiomyopathy in a Uruguayan family due to a codon deletion in a new location within the desmin 1A rod domain. Neuromuscul Disord 2010; 20:178-187. - 114.
Vicart P, Caron A, Guicheney P et al. A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy. Nat Genet 1998; 20:92–95. - 115.
Walter L, Nogueira V, Leverve X et al. Three classes of ubiquinone analogs regulate the mitochondrial permeability transition pore through a common site. J Biol Chem (2000); 275:29521-29527. - 116.
Watkins H, McKenna WJ, Thierfelder L, et al. Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med 1995;332:1058. - 117.
Wilde A, Bhuiyan Z, Crotti L et al Left cardiac sympathetic denervation for catecholaminergic polymorphic ventricular tachycardia. N Engl J Med. (2008); 358:2024– 2029. - 118.
Wolpert C, Veltmann C et al. Short QT syndrome. In Baars H, van der Smagt, J, Doevendans P, editors. Clinical Cardiogenetics: Springer 2011; p.189-196. - 119.
Zhang, J., Kumar, A., Stalker, H et al.Clinical and molecular studies of a large family with desmin-associated restrictive cardiomyopathy.Clin. Genet. 2001; 59:248-256. - 120.
Zhang J, Kumar A, Kaplan L et al. Genetic linkage of a novel autosomal dominant restrictive cardiomyopathy locus. J Med Genet 2005;42:663-665.