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PLoS One. 2017 Nov 9;12(11):e0187948. doi: 10.1371/journal.pone.0187948. eCollection 2017.

Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage.

Author information

1
Heart Lung Vascular Institute, Division of Cardiology, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America.
2
Department of Cell and Molecular Physiology, Center for Translational Research and Education, Health Sciences Division, Loyola University Chicago, Maywood, Illinois, United States of America.
3
Aurora Cardiovascular Services, St. Luke's Medical Center, Milwaukee, Wisconsin, United States of America.
4
Center for Integrative Research on Cardiovascular Aging (CIRCA), Aurora Health Care, Milwaukee, Wisconsin, United States of America.

Abstract

Over 1,500 gene mutations are known to cause hypertrophic cardiomyopathy (HCM). Previous studies suggest that cardiac β-myosin heavy chain (MYH7) gene mutations are commonly associated with a more severe phenotype, compared to cardiac myosin binding protein-C (MYBPC3) gene mutations with milder phenotype, incomplete penetrance and later age of onset. Compound mutations can worsen the phenotype. This study aimed to validate these comparative differences in a large cohort of individuals and families with HCM. We performed genome-phenome correlation among 80 symptomatic HCM patients, 35 asymptomatic carriers and 35 non-carriers, using an 18-gene clinical diagnostic HCM panel. A total of 125 mutations were identified in 14 genes. MYBPC3 and MYH7 mutations contributed to 50.0% and 24.4% of the HCM patients, respectively, suggesting that MYBPC3 mutations were the most frequent cause of HCM in our cohort. Double mutations were found in only nine HCM patients (7.8%) who were phenotypically indistinguishable from single-mutation carriers. Comparisons of clinical parameters of MYBPC3 and MYH7 mutants were not statistically significant, but asymptomatic carriers had high left ventricular ejection fraction and diastolic dysfunction when compared to non-carriers. The presence of double mutations increases the risk for symptomatic HCM with no change in severity, as determined in this study subset. The pathologic effects of MYBPC3 and MYH7 were found to be independent of gene mutation location. Furthermore, HCM pathology is independent of protein domain disruption in both MYBPC3 and MYH7. These data provide evidence that MYBPC3 mutations constitute the preeminent cause of HCM and that they are phenotypically indistinguishable from HCM caused by MYH7 mutations.

PMID:
29121657
PMCID:
PMC5679632
DOI:
10.1371/journal.pone.0187948
[Indexed for MEDLINE]
Free PMC Article

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