Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage
| Autor: | Aravindakshan Jagadeesan, Shiv Kumar Viswanathan, Arshad Jahangir, James W. McNamara, Sakthivel Sadayappan, A. Jamil Tajik, Heather Sanders |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Heredity lcsh:Medicine Penetrance Pathogenesis 030204 cardiovascular system & hematology Gene mutation medicine.disease_cause Pathology and Laboratory Medicine Severity of Illness Index Biochemistry 0302 clinical medicine Contractile Proteins Medicine and Health Sciences Frameshift Mutation lcsh:Science Genetics Mutation Multidisciplinary Hypertrophic cardiomyopathy Nonsense Mutation Middle Aged 3. Good health Phenotype cardiovascular system Female Research Article Adult Nonsense mutation Motor Proteins Cardiology Actin Motors macromolecular substances Biology Myosins Frameshift mutation 03 medical and health sciences Protein Domains Molecular Motors medicine Humans cardiovascular diseases Myosin Heavy Chains lcsh:R Biology and Life Sciences Proteins Cell Biology Cardiomyopathy Hypertrophic medicine.disease Cytoskeletal Proteins 030104 developmental biology Immunology MYH7 lcsh:Q Carrier Proteins Asymptomatic carrier Cardiac Myosins Ejection Fraction |
| Zdroj: | PLoS ONE, Vol 12, Iss 11, p e0187948 (2017) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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