Number 21, 2003
Hibernation preconditioning

Genetics of hypertrophic cardiomyopathy

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W.E.M. Kok¹, M.J.H. Baars^2
1Departments of Cardiology and
²Clinical and Human Genetics, VU University Medical Center, Amsterdam, The Netherlands
Correspondence: Dr W. Kok, Cardiology Department, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. e-mail: w.kok@vumc.nl

Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder, characterized by left ventricular hypertrophy, usually asymmetric in distribution, in the absence of other causes of hypertrophy (eg, systemic hypertension or aortic stenosis) [1]. It affects all ages, but usually becomes apparent from the age of adolescence, with a prevalence in young adults in the general population of 1 in 500 [2].
HCM is a genetically heterogeneous disease. Mutations have been detected in 11 cardiac sarcomere protein genes and in the CRP3/MLP gene coding for muscle-specific LIM protein [3–6]. HCM caused by sarcomere protein defects is characterized by cellular hypertrophy and myocyte disarray [3]. A hypertrophic appearance without these characteristics may be caused by disorders of storage disease, like Fabry's disease and a glycogen storage disease associated with the Wolff-Parkinson-White syndrome [3, 7].
The present review focuses on HCM caused by mutations in sarcomere protein genes. The cardiac sarcomere genes code for proteins building the structure of the sarcomere (Figure 1). At present, more than 200 different genetic mutations have been identified [3–5, 8]. All these mutations carry an autosomal-dominant inheritance pattern causing a familial hypertrophic cardiomyopathy [3–5]. A family history may not always be apparent; in unselected populations, a positive family history may be found in 50% [9]. Not all genetically similarly affected family members will have the same (or any) degree of disease, and penetrance (percent of carriers of the mutation who also have the disease) for some of the investigated mutations is in the order of 60% to 90% and is age-dependent [10–12].

Mutations in genes coding for sarcomere proteins
Three cardiac sarcomere protein genes are commonly (over 80%) mutated in hypertrophic cardiomyopathy: the β-myosin heavy chain, myosin-binding protein C, and cardiac troponin T genes [3, 5, 13]. The other genes account for a minority of cases of hypertrophic cardiomyopathy; they are summarized in Table I, together with estimated frequencies of their occurrence.
The β-myosin heavy chain gene, MYH7, is the largest of the cardiac sarcomere genes. It is composed of 40 exons (protein-coding parts of the gene, as opposed to introns, which are noncoding intervening parts between the exons), 38 of which are coding for a large protein of 1935 amino acids, carrying the myosin motor heads of the thick filaments [13]. The importance of the MYH7 gene in hypertrophic cardiomyopathy is manifested in the finding of at least 70 mutations in families with hypertrophic cardiomyopathy, with an early onset and a high (∼90%) penetrance of the disease [12–14]. Almost all the identified mutations in the MYH7 gene are missense mutations, resulting in a change of a single amino acid of the β-myosin heavy chain protein. The change may create a “poison peptide,” altering the function of the protein or its assembly into the sarcomere filaments [13]. Most mutations occur in the first part of the β-myosin heavy chain molecule, which contains the ATP binding site and the actin binding site, necessary for energy transfer and interaction between actin and myosin to enable contraction [13]. Arg403Gln and Arg719Gln mutations have been associated with a greater frequency of premature death than have other mutations [12, 14, 15].
The myosin-binding protein C gene, MYBPC3, is also a large cardiac sarcomere protein gene. It contains 35 exons, of which 34 are coding for 1173 amino acids for myosin binding protein C, which binds the myosin heavy chains and titin [13]. Of the more than 60 described MYBPC3 mutations, most occur in the latter part of the molecule, containing the major myosin and titin binding sites [5, 13]. In contrast to other gene mutations, MYBPC3 mutations often are deletions or insertions that result in a frame shift during translation [16]. The expected result is the creation of “truncated proteins,” missing at least the myosin binding domain [16]. Mutations in MYBPC3 have been characterized by a late onset and a mild phenotype [11, 17, 18].
The third most important gene, TNNT2 for cardiac troponin T, is composed of 17 exons coding for a cardiac sarcomere protein with the function of binding tropomyosin to the troponin complex, troponin C and troponin I, necessary for crossbridge kinetics [13]. More than 20 mutations, most often missense mutations, were found in families with hypertrophic cardiomyopathy [19–21]. The disease caused by TNNT2 mutations generally causes less severe hypertrophy, but has more severe myocyte disarray and carries a high risk of sudden cardiac death at young age [19–21].
Mutations that have been described in the eight other cardiac sarcomere genes, listed in Table I, explain a minority of cases of hypertrophic cardiomyopathy. They are most often missense mutations [13]. The results of several genotype–phenotype studies, including those of the more common gene mutations, suggest that some of these mutations cause more severe disease than others with regard to sudden cardiac death [4, 12, 14, 18, 20]. However, there is a significant degree of variability in clinical expression of a same mutation, and no particular clinical phenotype is mutation-specific [22].

Genetic counseling for patients with hypertrophic cardiomyopathy
When confronted with a patient with hypertrophic cardiomyopathy, a cardiologist should inform the patient concerning the nature of the disease, and its probable mode of inheritance. Some clues for risk assessment may be evident from making a pedigree, specifically asking about relatives with sudden cardiac death. Cardiologists should be aware of the diagnostic ability of genetic analysis, by which about 60% of genetic causes for hypertrophic cardiomyopathy may be determined, even in “sporadic” cases without an apparent family history [5, 23]. Other causes of hypertrophic cardiomyopathy-like disorders may have to be excluded such as hyperparathyroidism, M. Fabry, von Recklinghausen neurofibromatosis, Friedreich's ataxia, mitochondrial cardiomyopathy, Noonan syndrome, and storage diseases such as hemochromatosis and amyloidosis [3]. Laboratory evaluation and sometimes neurological evaluation may therefore be of use when in doubt about the nature of cardiac hypertrophy.
As part of genetic counseling, patients and relatives should be well informed about the consequences of a possible genetic diagnosis [24]. When patients or their relatives consent to further genetic analysis, it is cost-effective first to screen the index patient for defects in the most frequently mutated genes, MYH7 and MYBPC3. In severe cases of hypertrophic cardiomyopathy, compound heterozygotic mutations should be considered [25]. At present, the additional value of a genetic diagnosis is rather small, for example to reassure family members who do not possess the mutation, or to give advice on participation in competitive sports [24]. When sudden cardiac death occurs within a family with hypertrophic cardiomyopathy, the possible benefit from an implantable cardiac defibrillator must be considered in family members with the same genotype [26].
As protein defects in hypertrophic cardiomyopathy in themselves do not cause hypertrophy [27], life-style factors, modifier genes and polymorphisms that could modulate the phenotypic expression of the disease are being investigated [12, 22]. An early genetic diagnosis in a person with familial hypertrophic cardiomyopathy may therefore also be of value in enabling the institution, at younger age, of therapeutic strategies that include treatment with hydroxymethyl glutaryl-coenzyme A reductase inhibitors and angiotensin-converting enzyme inhibitors, which have shown promise in animal models of hypertrophic cardiomyopathy [28, 29].▪

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REFERENCES

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