Original Article
Sarcomeric Genotyping in Hypertrophic Cardiomyopathy

https://doi.org/10.4065/80.4.463Get rights and content

OBJECTIVE

To pool results from studies of patients with hypertrophic cardiomyopathy (HCM) to elucidate important phenotypic differences among genotypes.

PATIENTS AND METHODS

Data published from November 1998 through November 2004 were gathered and compared from unrelated study population genotyping studies from the Mayo Clinic (Rochester, Minn), Harvard Medical School (Boston, Mass), France, Germany, Sweden, Finland, and Spain. Standard statistical analysis techniques were used to pool and compare data across genotypes with respect to frequency of mutations, age at diagnosis, and degree of hypertrophy (left ventricular wall thickness).

RESULTS

The French study population harbored the highest frequency of mutations (61%), followed by the Mayo Clinic (38%), Harvard Medical School (36%), and Swedish (30%) study populations. For every study population, mutations in myosin binding protein C (MYBPC3) were the most common cause of HCM. Patients with a family history of HCM had mutations more frequently than those without. This pooled analysis revealed no statistically significant differences in left ventricular wall thickness or in mean age at diagnosis across all genotypes.

CONCLUSIONS

Differentiation of sarcomeric genotypes, such as MYBPC3-HCM and MYH7-HCM, is not possible on the basis of currently reported phenotypic data. A myriad of genetic and/or environmental modifiers in addition to the primary disease-causing genetic substrate must play an important role in determining a patient's particular phenotype.

Section snippets

MATERIAL AND METHODS

Review of PubMed and MEDLINE search results revealed several studies published in the English language of large groups of unrelated patients with HCM who had been genotyped for sarcomeric mutations. Data published from November 1998 through November 2004 were gathered and compared from unrelated study population genotyping studies from the Mayo Clinic (Rochester, Minn),11, 22, 23, 24, 25 Harvard Medical School (Boston, Mass),26 France,10 Germany,27 Sweden,28 Spain,29 and Finland.30, 31, 32, 33

Study Population Analyses

Table 1 summarizes the clinical characteristics of each study population analyzed, except for the Harvard study population for whom data were not available. Study population size, genes screened, and methods used are summarized in Table 2. Note that the Mayo Clinic and French studies reported complete analysis of each of the 8 sarcomeric genes; the Harvard and Swedish studies reported complete analysis of all but MYH7, which was analyzed in part; and the German, Finnish, and Spanish studies

Study Population Analyses

Because each study population is clinically unique, extrapolations from any individual study population to the general HCM population must be made judiciously. Specifically, patients from tertiary referral centers for HCM may not be representative of the general HCM population. Of the 2 largest study populations, the Mayo Clinic HCM study population is overrepresented by patients treated surgically for left ventricular outflow obstruction, and the French study population overwhelmingly

CONCLUSIONS

Several conclusions can be drawn pertaining to the cardiac sarcomere gene screen in the evaluation of HCM. First, although HCM has been coined the “disease of the sarcomere,” more than half of unrelated patients will have no identifiable HCM-associated variant among the currently known sarcomere genes implicated in the pathogenesis of HCM. Novel genetic and/or environmental causes of this disease must be elucidated to determine the pathogenic mechanisms at work in patients with nonsarcomeric

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    This study was supported by a Mayo Foundation clinical research award to Dr Ackerman. Dr Ackerman is an established investigator of the American Heart Association.

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