Hypertrophic cardiomyopathy genetics
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
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 <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>. Children of a patient with HCM have a 50% chance of inheriting the trait.
Mutations
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 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.
Genetics
HCM is the most common genetically transmitted cardiovascular disease. 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 70 mutations involving at least 7 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.
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. Currently there are more than 400 mutations in these genes. 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 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 [1] [2].
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.
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.
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 (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.
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 [3] .[4]
References
- ↑ 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)
- ↑ Doolan G, Nguyen L, Chung J, Ingles J, Semsarian C (2004). "Progression of left ventricular hypertrophy and the angiotensin-converting enzyme gene polymorphism in hypertrophic cardiomyopathy". Int J Cardiol. 96 (2): 157–63. doi:10.1016/j.ijcard.2004.05.003. PMID 15314809. Unknown parameter
|month=ignored (help) - ↑ Marian AJ, Yu QT, Workman R, Greve G, Roberts R (1993). "Angiotensin-converting enzyme polymorphism in hypertrophic cardiomyopathy and sudden cardiac death". Lancet. 342 (8879): 1085–6. doi:10.1016/0140-6736(93)92064-Z. PMID 8105312. Unknown parameter
|month=ignored (help)