Myofilament Protein Gene Mutation Screening and Outcome of Patients With Hypertrophic Cardiomyopathy

doi:10.4065/83.6.630

Mayo Clinic Proceedings

Volume 83, Issue 6, June 2008, Pages 630-638

https://doi.org/10.4065/83.6.630 Get rights and content

OBJECTIVE

To determine the influence of a positive genetic test for hypertrophic cardiomyopathy (HCM) on clinical outcome.

PATIENTS AND METHODS

A cohort of 203 unrelated patients with HCM (mean ± SD age, 50±18 years) was enrolled from January 1, 2002, through December 31, 2003. They were followed up for a mean ± SD time of 4.0±1.7 years after genetic testing of the 8 HCM-susceptibility genes that encode key sarcomeric/myofilament proteins. The clinical phenotype of those with a positive genetic test (myofilament-positive HCM) was compared with those with a negative genetic test (myofilament-negative HCM).

RESULTS

In this cohort of 203 patients, 87 mutations were identified in 126 patients (myofilament-positive HCM, 62%); the remaining 77 patients (38%) were myofilament-negative. Despite similar baseline features, patients with myofilament-positive HCM showed increased risk of the combined end points of cardiovascular death, nonfatal stroke, or progression to New York Heart Association class III or IV compared with the patients with myofilament-negative HCM (25% vs 7%, respectively; independent hazard ratio, 4.27; P=.008). These end points occurred at any age among patients with myofilament-positive HCM (range, 14-86 years), but only in those aged 65 years and older among patients with myofilament-negative HCM. Moreover, patients with myofilament-positive HCM showed greater probability of severe left ventricular systolic and diastolic dysfunction, defined as an ejection fraction of less than 50% and a restrictive filling pattern (P=.02 and P<.02, respectively, vs myofilament-negative HCM).

CONCLUSION

Screening for sarcomere protein gene mutations in HCM identifies a broad subgroup of patients with increased propensity toward long-term impairment of left ventricular function and adverse outcome, irrespective of the myofilament (thick, intermediate, or thin) involved.

Section snippets

PATIENTS AND METHODS

The study included 203 unrelated index patients with a confirmed clinical diagnosis of HCM, consecutively enrolled at the Azienda Ospedaliera-Universitaria Careggi, in Florence, Italy, and Ospedale San Camillo, in Rome, Italy, since the beginning of a systematic screeningprogram for myofilament gene mutations.¹³ Patients were enrolled from January 1, 2002, through December 31, 2003. The study patients had already been diagnosed as having HCM and were followed up for a median of 4.1 years before

Comprehensive Mutational Analysis

In 126 (62%) of the 203 study patients, we identified 87 distinct mutations, of which 51 were classified as novel (Figure 1, Table 2). These 126 patients were considered to have myofilament-positive HCM. The remaining 77 patients (38%) had no discernible myofilament mutations and were considered to have myofilament-negative HCM. The most frequent disease-associated gene was MYBPC3 (n=68; 34%; including 9 patients with double mutations in this gene). The MYBPC3 E258K mutation, which was found in

DISCUSSION

Our study shows that the identification of 1 or more cardiac myofilament gene mutations is associated with increased risk of LV dysfunction and adverse outcome due to heart failure in patients with HCM. In our cohort, myofilament-positive HCM was characterized by an almost 30% prevalence of severe systolic and/or diastolic LV dysfunction, which was increasingly common after the fourth decade of life and occurred at a similar rate for each of the 3 major myofilament subtypes involved. By

CONCLUSION

Hypertrophic cardiomyopathy due to myofilament gene mutations is characterized by adverse outcome and more frequent derangement of LV function compared with myofilament-negative disease, irrespective of the myofilament type involved. These findings support a clinical and prognostic role for genetic testing in patients with clinically diagnosed HCM.

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: This study was supported by grants from the Italian Ministry for Scientific and Technologic Research (MURST - COFIN 2004), the Fondazione Ente Cassa di Risparmio di Firenze, and the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.

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ORIGINAL ARTICLEMyofilament Protein Gene Mutation Screening and Outcome of Patients With Hypertrophic Cardiomyopathy

OBJECTIVE

PATIENTS AND METHODS

RESULTS

CONCLUSION

Section snippets

PATIENTS AND METHODS

Comprehensive Mutational Analysis

DISCUSSION

CONCLUSION

J Am Coll Cardiol

A contemporary approach to hypertrophic cardiomyopathy

Circulation

Hypertrophic cardiomyopathy

Lancet

Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy

Circulation

Mutational spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy

Clin Genet

Prevalence and spectrum of thin filament mutations in an outpatient referral population with hypertrophic cardiomyopathy

Circulation

Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy

J Am Coll Cardiol

Familial hypertrophic cardiomyopathy: clinical features, molecular genetics and molecular genetic testing

Expert Rev Mol Diagn

Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere

Cell

Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy

N Engl J Med

Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy

N Engl J Med

Sudden death due to troponin T mutations

J Am Coll Cardiol

Prevalence and clinical profile of troponin T mutations among patients with hypertrophic cardiomyopathy in Tuscany

Am J Cardiol

Prevalence and age-dependence of malignant mutations in the beta-myosin heavy chain and troponin T genes in hypertrophic cardiomyopathy: a comprehensive outpatient perspective

J Am Coll Cardiol

Echocardiography-guided genetic testing in hypertrophic cardiomyopathy: septal morphological features predict the presence of myofilament mutations

Mayo Clin Proc

Denaturing high-performance liquid chromatography: a review

Hum Mutat

Denaturing high performance liquid chromatography: high throughput mutation screening in familial hypertrophic cardiomyopathy and SNP genotyping in motor neurone disease

J Clin Pathol

Quality control in the discovery, reporting, and recording of genomic variation

Hum Mutat

Hypertrophic cardiomyopathy in Tuscany: clinical course and outcome in an unselected regional population

J Am Coll Cardiol

ORIGINAL ARTICLE
Myofilament Protein Gene Mutation Screening and Outcome of Patients With Hypertrophic Cardiomyopathy