Hypertrophic cardiomyopathy genetics
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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
- ↑ 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.
- ↑ Schwartz K, Carrier L, Guicheney P, Komajda M. Molecular basis of familial cardiomyopathies. Circulation 1995;91:532–40.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Marian AJ, Roberts R. Recent advances in the molecular genetics of hypertrophic cardiomyopathy. Circulation 1995;92:1336–47.
- ↑ Niimura H, Patton KK, McKenna WJ et al. Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation 2002;105:446–51.
- ↑ Seidman JG, Seidman CE. The genetic basis for cardiomyopathy. From mutation identification to mechanistic paradigms. Cell 2001; 104:557–67.
- ↑ 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.
- ↑ 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)
- ↑ 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)