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{{Hypertrophic cardiomyopathy}}
{{Hypertrophic cardiomyopathy}}
{{CMG}}
{{CMG}}; {{AOEIC}} {{LG}}


==Overview==
==Overview==
HCM is the most common genetically transmitted cardiovascular disease.  Hypertrophic cardiomyopathy is inherited as an [[autosomal dominant]] trait and is attributed to mutations in one of a number of genes that encode for one of the [[sarcomere]] [[protein]]s <ref>Maron BJ, Moller JH, Seidman CE et al. Impact of laboratory molecular diagnosis on contemporary diagnostic criteria for genetically transmitted cardiovascular diseases. Hypertrophic cardiomyopathy, long-QT syndrome, and Marfan syndrome. [A statement for healthcare professionals from the Councils on Clinical Cardiology, Cardiovascular Disease in the Young, and Basic Science, American Heart Association]. Circulation 1998;98:1460–71.</ref><ref>Schwartz K, Carrier L, Guicheney P, Komajda M. Molecular basis of familial cardiomyopathies. Circulation 1995;91:532–40.</ref><ref>Niimura H, Bachinski LL, 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.</ref><ref>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;77:701–12.</ref><ref>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;332:1058–64.</ref><ref>Charron P, Dubourg O, Desnos M et al. Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin-binding protein C gene. Circulation 1998;97: 2230–6.</ref><ref>Maron BJ, Niimura H, Casey SA et al. Development of left ventricular hypertrophy in adults in hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations. J Am Coll Cardiol 2001;38:315–21.</ref><ref>Anan R, Greve G, Thierfelder L et al. Prognostic implications of novel beta cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy. J Clin Invest 1994;93:280–5.</ref><ref>Coviello DA, Maron BJ, Spirito P et al. Clinical features of hypertrophic cardiomyopathy caused by mutation of a “hot spot” in the alpha-tropomyosin gene. J Am Coll Cardiol 1997;29:635–40.</ref><ref>Blair E, Redwood C, Ashrafian H et al. Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy. Evidence for the central role of energy compromise in disease pathogenesis. Hum Mol Genet 2001;10:1215–20.</ref><ref>Erdmann J, Raible J, Maki-Abadi J et al. Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy. J Am Coll Cardiol 2001;38:322–30.</ref><ref>Gruver EJ, Fatkin D, Dodds GA et al. Familial hypertrophic cardiomyopathy and atrial fibrillation caused by Arg663His beta-cardiac myosin heavy chain mutation. Am J Cardiol 1999;83:13H–8H.</ref><ref>Kimura A, Harada H, Park JE et al. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nat Genet 1997;16:379–82.</ref><ref>Marian AJ, Roberts R. Recent advances in the molecular genetics of hypertrophic cardiomyopathy. Circulation 1995;92:1336–47.</ref><ref>Niimura H, Patton KK, McKenna WJ et al. Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation 2002;105:446–51.</ref>.  Penetrance of HCM is incomplete and age-related.  The disease may be sporadic but affected family members are discovered in 13% of cases.  More than 200 mutations involving at least 10 chromosomes encoding structural proteins of the myocyte have been discovered.  These mutations have varying degrees of penetrance and even the same mutation may have variable expression, implying superimposed effects of other genes or environmental influences.  Children of a patient with HCM have a 50% chance of inheriting the trait.
HCM is the most common genetically transmitted cardiovascular disease.  Hypertrophic cardiomyopathy is inherited as an [[autosomal dominant]] trait and is attributed to mutations in one of a number of genes that encode for one of the [[sarcomere]] [[protein]]s <ref>Maron BJ, Moller JH, Seidman CE et al. Impact of laboratory molecular diagnosis on contemporary diagnostic criteria for genetically transmitted cardiovascular diseases. Hypertrophic cardiomyopathy, long-QT syndrome, and Marfan syndrome. [A statement for healthcare professionals from the Councils on Clinical Cardiology, Cardiovascular Disease in the Young, and Basic Science, American Heart Association]. Circulation 1998;98:1460–71.</ref><ref>Schwartz K, Carrier L, Guicheney P, Komajda M. Molecular basis of familial cardiomyopathies. Circulation 1995;91:532–40.</ref><ref>Niimura H, Bachinski LL, 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.</ref><ref>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;77:701–12.</ref><ref>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;332:1058–64.</ref><ref>Charron P, Dubourg O, Desnos M et al. Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin-binding protein C gene. Circulation 1998;97: 2230–6.</ref><ref>Maron BJ, Niimura H, Casey SA et al. Development of left ventricular hypertrophy in adults in hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations. J Am Coll Cardiol 2001;38:315–21.</ref><ref>Anan R, Greve G, Thierfelder L et al. Prognostic implications of novel beta cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy. J Clin Invest 1994;93:280–5.</ref><ref>Coviello DA, Maron BJ, Spirito P et al. Clinical features of hypertrophic cardiomyopathy caused by mutation of a “hot spot” in the alpha-tropomyosin gene. J Am Coll Cardiol 1997;29:635–40.</ref><ref>Blair E, Redwood C, Ashrafian H et al. Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy. Evidence for the central role of energy compromise in disease pathogenesis. Hum Mol Genet 2001;10:1215–20.</ref><ref>Erdmann J, Raible J, Maki-Abadi J et al. Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy. J Am Coll Cardiol 2001;38:322–30.</ref><ref>Gruver EJ, Fatkin D, Dodds GA et al. Familial hypertrophic cardiomyopathy and atrial fibrillation caused by Arg663His beta-cardiac myosin heavy chain mutation. Am J Cardiol 1999;83:13H–8H.</ref><ref>Kimura A, Harada H, Park JE et al. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nat Genet 1997;16:379–82.</ref><ref>Marian AJ, Roberts R. Recent advances in the molecular genetics of hypertrophic cardiomyopathy. Circulation 1995;92:1336–47.</ref><ref>Niimura H, Patton KK, McKenna WJ et al. Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation 2002;105:446–51.</ref>.  Penetrance of HCM is incomplete, variable and time or age-related.  The disease may be sporadic but affected family members are discovered in 13% of cases.  More than 200 mutations involving at least 10 chromosomes encoding structural proteins of the myocyte have been discovered.  These mutations have varying degrees of penetrance and even the same mutation may have variable expression, implying superimposed effects of other genes or environmental influences.  Children of a patient with HCM have a 50% chance of inheriting the trait.


==Mutations==
==Mutations==
===Common Mutations===
===Common Mutations===
Mutations in three regions compromise more than half the abnormalities:
Mutations in three regions affect more than half the patients with HCM:
*Beta-myosin heavy chain
*Beta-myosin heavy chain
*Myosin binding protein C
*Myosin binding protein C
Line 14: Line 20:


===Complete List of Mutations===
===Complete List of Mutations===
Specific gene mutations that have been identified include the following:
Hypertrophic cardiomyopathy is inherited as an [[autosomal dominant]] trait and is attributed to mutations in one of a number of genes that encode for one of the [[sarcomere]] [[protein]]s including beta-cardiac myosin heavy chain (the first gene identified), cardiac actin, [[troponin T|cardiac troponin T]], alpha-tropomyosin, [[troponin I|cardiac troponin I]], cardiac myosin-binding protein C, and the myosin light chains.  Specific gene mutations that have been identified include the following:


{| class="wikitable" class="sortable wikitable"
{| class="wikitable" class="sortable wikitable"
Line 76: Line 82:
While most literature so far focuses on European, American, and Japanese populations, HCM appears in all racial groups. The incidence of HCM is about 0.2% to 0.5% of the general population.
While most literature so far focuses on European, American, and Japanese populations, HCM appears in all racial groups. The incidence of HCM is about 0.2% to 0.5% of the general population.


==Specific Mutations==
==Specific Chromosomal Abnormalities==
===β [[Myosin]] Heavy Chain-Chromosome 14 q11.2-3===
In individuals without a family history of HCM, the most common cause of the disease is a [[mutation|de novo mutation]] of the gene that produces the β-myosin heavy chain.  This chromosomal abnormality accounts for approximately 35%-45% of HCM cases. Significant [[LVH]] ([[left ventricular hypertrophy]]) is usually presnet.  The Arg403Gln mutation is associated with an extremely poor prognosis with average age of death at 33 years, while the Val606Met mutation is associated with a better prognosis.
 
====Cardiac Troponin T-Chromosome 11====
Accounts for approximately 15% of cases. Substantially less hypertrophy is noted but histology demonstrates the characteristic myocyte disarray of HCM. Most mutations of this gene are associated with markedly reduced survival.
 
===Cardiac Myosin Binding Protein-C-Chromosome 11===
This chromosomal abnormality accounts for 15% to 35% of patients, but given the reduced penetrance associated with this abnormality, the true incidence may actually be greater.  Patients generally present later in life and in general, have a better prognosis than beta myosin heavy chain or cardiac troponin T mutations.  Up to 60% of patients at age 50 years have no  evidence of [[LVH]].  LVH may appear later in life in these patients. Because of this, a normal EKG and a normal ECHO at age 18 does not exclude the presence of HCM.
 
===Arg663 His mutation===
===Arg663 His mutation===
The beta-myosin heavy chain Arg663 His mutation is associated with a higher risk of [[atrial fibrillation]] <ref>Seidman JG, Seidman CE. The genetic basis for cardiomyopathy.
The beta-myosin heavy chain Arg663 His mutation is associated with a higher risk of [[atrial fibrillation]] <ref>Seidman JG, Seidman CE. The genetic basis for cardiomyopathy.
Line 83: Line 98:


===PRKAG2 Mutation===
===PRKAG2 Mutation===
There is no myocyte disarray, there is conduction block. This variant is more akin to a storage disease<ref>Arad M, Benson DW, Perez-Atayde AR et al. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J Clin Invest 2002;109:357–62.</ref>.
There is no myocyte disarray, but conduction block is present. This variant is more akin to a storage disease<ref>Arad M, Benson DW, Perez-Atayde AR et al. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J Clin Invest 2002;109:357–62.</ref>.
 
==Genetics==
The prognosis is variable, based on the gene mutation. In individuals without a family history of HCM, the most common cause of the disease is a [[mutation|de novo mutation]] of the gene that produces the β-myosin heavy chain.
 
An insertion/deletion polymorphism in the [[gene]] encoding for [[angiotensin converting enzyme]] (ACE) alters the clinical [[phenotype]] of the disease. The D/D (deletion/deletion) genotype of ACE is associated with more marked hypertrophy of the left ventricle and may be associated with higher risk of adverse outcomes
<ref name="Doolan, Nguyen et al 2004">Doolan G, Nguyen L, Chung J, Ingles J, Semsarian C. Progression of left ventricular hypertrophy and the angiotensin-converting enzyme gene polymorphism in hypertrophic cardiomyopathy. ''Int J Cardiol''. 2004 Aug; '''96'''(2):157–63. ([http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15314809 Medline abstract])</ref> <ref name="Marian, Yu et al 1993">Marian AJ, Yu QT, Workman R, Greve G, Roberts R. Angiotensin-converting enzyme polymorphism in hypertrophic cardiomyopathy and sudden cardiac death. ''Lancet''. 1993 Oct 30; '''342'''(8879):1085–6. ([http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8105312 Medline abstract])</ref>.
 
There are some genetic variants that yield a normal wall thickness.
 
===Specific Chromosomal Abnormalities===
 
====β [[Myosin]] Heavy Chain-Chromosome 14 q11.2-3====
 
Accounts for approximately 35%-45% of cases. Significant [[LVH]] ([[left ventricular hypertrophy]]) is usually noted.  The Arg403Gln mutation is associated with an extremely poor prognosis with average age of death at 33 years, while the Val606Met mutation is associated with a better prognosis.
 
====Cardiac Myosin Binding Protein-C-Chromosome 11==== 


Accounts for another 15%-35% but has a reduced penetrance so may actually be more. Patients generally present later in life and in general, have a better prognosis than with the prior 2 mutations. Up to 60% at age 50 years have no [[LVH]].  
==Mutations that Alter the Phenotypic Expression of the Disease==
An insertion/deletion polymorphism in the [[gene]] encoding for [[angiotensin converting enzyme]] (ACE) alters the clinical [[phenotype]] of the disease. The D/D (deletion/deletion) genotype of ACE is associated with more marked hypertrophy of the left ventricle and may be associated with higher risk of adverse outcomes <ref name="Doolan, Nguyen et al 2004">Doolan G, Nguyen L, Chung J, Ingles J, Semsarian C. Progression of left ventricular hypertrophy and the angiotensin-converting enzyme gene polymorphism in hypertrophic cardiomyopathy. ''Int J Cardiol''. 2004 Aug; '''96'''(2):157–63. ([http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15314809 Medline abstract])</ref> <ref name="Marian, Yu et al 1993">Marian AJ, Yu QT, Workman R, Greve G, Roberts R. Angiotensin-converting enzyme polymorphism in hypertrophic cardiomyopathy and sudden cardiac death. ''Lancet''. 1993 Oct 30; '''342'''(8879):1085–6. ([http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8105312 Medline abstract])</ref>.


====Cardiac Troponin T-Chromosome 11====
==Genetic Testing==
 
Whenever a mutation is identified through genetic testing, family-specific genetic testing can be used to identify relatives at-risk for the disease ([http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hyper-card#hyper-card HCM Genetic Testing Overview]). In individuals without a family history of HCM, the most common cause of the disease is a [[mutation|de novo mutation]] of the gene that produces the β-myosin heavy chain.
Accounts for approximately 15% of cases. Substantially less hypertrophy is noted but histology demonstrates the characteristic myocyte disarray of HCM. Most mutations of this gene are associated with markedly reduced survival.
 
====Other Genetic Abnormalities====
 
Other genes encoding alpha tropomyosin, myosin regulatory light chain, cardiac [[troponin I]] and cardiac [[troponin C]] have been implicated. A mutation on Chromosome 7 is associated with HCM and the [[WPW]] ([[Wolff-Parkinson-White syndrome]]).
About 50-60% of patients with a high index of clinical suspicion for HCM will have a mutation identified in at least 1 of 9 sarcomeric genes. Approximately 45% of these mutations occur in the β [[myosin]] heavy chain gene on [[chromosome]] 14 q11.2-3, while approximately 35% involve the cardiac myosin binding protein C gene. Since HCM is typically an [[autosomal dominant]] trait, children of an HCM parent have 50% chance of inheriting the disease-causing mutation. Whenever a mutation is identified through genetic testing, family-specific genetic testing can be used to identify relatives at-risk for the disease ([http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hyper-card#hyper-card HCM Genetic Testing Overview]). In individuals without a family history of HCM, the most common cause of the disease is a [[mutation|de novo mutation]] of the gene that produces the β-myosin heavy chain.
 
An insertion/deletion polymorphism in the [[gene]] encoding for [[angiotensin converting enzyme]] (ACE) alters the clinical [[phenotype]] of the disease. The D/D (deletion/deletion) genotype of ACE is associated with more marked hypertrophy of the left ventricle and may be associated with higher risk of adverse outcomes
<ref name="Doolan, Nguyen et al. 2004">{{cite journal |author=Doolan G, Nguyen L, Chung J, Ingles J, Semsarian C |title=Progression of left ventricular hypertrophy and the angiotensin-converting enzyme gene polymorphism in hypertrophic cardiomyopathy |journal=Int J Cardiol |volume=96 |issue=2 |pages=157–63 |year=2004 |month=Aug |pmid=15314809 |doi=10.1016/j.ijcard.2004.05.003 }}</ref>
.<ref name="Marian, Yu et al. 1993">{{cite journal |author=Marian AJ, Yu QT, Workman R, Greve G, Roberts R |title=Angiotensin-converting enzyme polymorphism in hypertrophic cardiomyopathy and sudden cardiac death |journal=Lancet |volume=342 |issue=8879 |pages=1085–6 |year=1993 |month=Oct |pmid=8105312 |doi= 10.1016/0140-6736(93)92064-Z|url=http://linkinghub.elsevier.com/retrieve/pii/0140-6736(93)92064-Z}}</ref>


==References==
==References==
{{Reflist|2}}
{{reflist|2}}


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Lakshmi Gopalakrishnan, M.B.B.S. [2]

Overview

HCM is the most common genetically transmitted cardiovascular disease. Hypertrophic cardiomyopathy is inherited as an autosomal dominant trait and is attributed to mutations in one of a number of genes that encode for one of the sarcomere proteins [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. Penetrance of HCM is incomplete, variable and time or age-related. The disease may be sporadic but affected family members are discovered in 13% of cases. More than 200 mutations involving at least 10 chromosomes encoding structural proteins of the myocyte have been discovered. These mutations have varying degrees of penetrance and even the same mutation may have variable expression, implying superimposed effects of other genes or environmental influences. Children of a patient with HCM have a 50% chance of inheriting the trait.

Mutations

Common Mutations

Mutations in three regions affect more than half the patients with HCM:

  • Beta-myosin heavy chain
  • Myosin binding protein C
  • Cardiac troponin T

Complete List of Mutations

Hypertrophic cardiomyopathy is inherited as an autosomal dominant trait and is attributed to mutations in one of a number of genes that encode for one of the sarcomere proteins including beta-cardiac myosin heavy chain (the first gene identified), cardiac actin, cardiac troponin T, alpha-tropomyosin, cardiac troponin I, cardiac myosin-binding protein C, and the myosin light chains. Specific gene mutations that have been identified include the following:

Gene Locus Type
MYH7 14q12 CMH1
TNNT2 1q32 CMH2
TPM1 15q22.1 CMH3 (115196)
MYBPC3 11p11.2 CMH4 (115197)
? ? CMH5
PRKAG2 7q36 CMH6 (600858)
TNNI3 19q13.4 CMH7
MYL3 3p CMH8 (608751)
TTN 2q24.3 CMH9
MYL2 12q23-q24 CMH10
ACTC1 15q14 CMH11 (612098)
CSRP3 11p15.1 CMH12 (612124)

While the above table represents the most common genetic mutations, there are also about 200 intergenic (within a gene) mutations. These include missense and single amino acid residue substitutions. There are different genetic mutations in different families. Environment may also play a role because affected inidiviudals in the same family may have different phenotypic expression (i.e different degrees of left ventricular hypertrophy). The goal of modifier genes in regulating phenotypic expression is not clear.

While genes, gene modifiers and environment may play a role in the phenotypic expression of left ventricular hypertrophy, genes may also play a role in the risk of arrhythmias. While most literature so far focuses on European, American, and Japanese populations, HCM appears in all racial groups. The incidence of HCM is about 0.2% to 0.5% of the general population.

Specific Chromosomal Abnormalities

β Myosin Heavy Chain-Chromosome 14 q11.2-3

In individuals without a family history of HCM, the most common cause of the disease is a de novo mutation of the gene that produces the β-myosin heavy chain. This chromosomal abnormality accounts for approximately 35%-45% of HCM cases. Significant LVH (left ventricular hypertrophy) is usually presnet. The Arg403Gln mutation is associated with an extremely poor prognosis with average age of death at 33 years, while the Val606Met mutation is associated with a better prognosis.

Cardiac Troponin T-Chromosome 11

Accounts for approximately 15% of cases. Substantially less hypertrophy is noted but histology demonstrates the characteristic myocyte disarray of HCM. Most mutations of this gene are associated with markedly reduced survival.

Cardiac Myosin Binding Protein-C-Chromosome 11

This chromosomal abnormality accounts for 15% to 35% of patients, but given the reduced penetrance associated with this abnormality, the true incidence may actually be greater. Patients generally present later in life and in general, have a better prognosis than beta myosin heavy chain or cardiac troponin T mutations. Up to 60% of patients at age 50 years have no evidence of LVH. LVH may appear later in life in these patients. Because of this, a normal EKG and a normal ECHO at age 18 does not exclude the presence of HCM.

Arg663 His mutation

The beta-myosin heavy chain Arg663 His mutation is associated with a higher risk of atrial fibrillation [16].

PRKAG2 Mutation

There is no myocyte disarray, but conduction block is present. This variant is more akin to a storage disease[17].

Mutations that Alter the Phenotypic Expression of the Disease

An insertion/deletion polymorphism in the gene encoding for angiotensin converting enzyme (ACE) alters the clinical phenotype of the disease. The D/D (deletion/deletion) genotype of ACE is associated with more marked hypertrophy of the left ventricle and may be associated with higher risk of adverse outcomes [18] [19].

Genetic Testing

Whenever a mutation is identified through genetic testing, family-specific genetic testing can be used to identify relatives at-risk for the disease (HCM Genetic Testing Overview). In individuals without a family history of HCM, the most common cause of the disease is a de novo mutation of the gene that produces the β-myosin heavy chain.

References

  1. ↑ Maron BJ, Moller JH, Seidman CE et al. Impact of laboratory molecular diagnosis on contemporary diagnostic criteria for genetically transmitted cardiovascular diseases. Hypertrophic cardiomyopathy, long-QT syndrome, and Marfan syndrome. [A statement for healthcare professionals from the Councils on Clinical Cardiology, Cardiovascular Disease in the Young, and Basic Science, American Heart Association]. Circulation 1998;98:1460–71.
  2. ↑ Schwartz K, Carrier L, Guicheney P, Komajda M. Molecular basis of familial cardiomyopathies. Circulation 1995;91:532–40.
  3. ↑ Niimura H, Bachinski LL, 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.
  4. ↑ 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;77:701–12.
  5. ↑ 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;332:1058–64.
  6. ↑ Charron P, Dubourg O, Desnos M et al. Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin-binding protein C gene. Circulation 1998;97: 2230–6.
  7. ↑ Maron BJ, Niimura H, Casey SA et al. Development of left ventricular hypertrophy in adults in hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations. J Am Coll Cardiol 2001;38:315–21.
  8. ↑ Anan R, Greve G, Thierfelder L et al. Prognostic implications of novel beta cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy. J Clin Invest 1994;93:280–5.
  9. ↑ Coviello DA, Maron BJ, Spirito P et al. Clinical features of hypertrophic cardiomyopathy caused by mutation of a “hot spot” in the alpha-tropomyosin gene. J Am Coll Cardiol 1997;29:635–40.
  10. ↑ Blair E, Redwood C, Ashrafian H et al. Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy. Evidence for the central role of energy compromise in disease pathogenesis. Hum Mol Genet 2001;10:1215–20.
  11. ↑ Erdmann J, Raible J, Maki-Abadi J et al. Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy. J Am Coll Cardiol 2001;38:322–30.
  12. ↑ Gruver EJ, Fatkin D, Dodds GA et al. Familial hypertrophic cardiomyopathy and atrial fibrillation caused by Arg663His beta-cardiac myosin heavy chain mutation. Am J Cardiol 1999;83:13H–8H.
  13. ↑ Kimura A, Harada H, Park JE et al. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nat Genet 1997;16:379–82.
  14. ↑ Marian AJ, Roberts R. Recent advances in the molecular genetics of hypertrophic cardiomyopathy. Circulation 1995;92:1336–47.
  15. ↑ Niimura H, Patton KK, McKenna WJ et al. Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation 2002;105:446–51.
  16. ↑ Seidman JG, Seidman CE. The genetic basis for cardiomyopathy. From mutation identification to mechanistic paradigms. Cell 2001; 104:557–67.
  17. ↑ Arad M, Benson DW, Perez-Atayde AR et al. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J Clin Invest 2002;109:357–62.
  18. ↑ Doolan G, Nguyen L, Chung J, Ingles J, Semsarian C. Progression of left ventricular hypertrophy and the angiotensin-converting enzyme gene polymorphism in hypertrophic cardiomyopathy. Int J Cardiol. 2004 Aug; 96(2):157–63. (Medline abstract)
  19. ↑ Marian AJ, Yu QT, Workman R, Greve G, Roberts R. Angiotensin-converting enzyme polymorphism in hypertrophic cardiomyopathy and sudden cardiac death. Lancet. 1993 Oct 30; 342(8879):1085–6. (Medline abstract)


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