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Updated: May 30, 2026
Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Genetic screening and double mutation in Japanese patients with hypertrophic cardiomyopathy
Toru Kubo1, Hiroaki Kitaoka, Makoto Okawa
1Department of Medicine and Geriatrics, Kochi Medical School, Tokyo, Japan.
Insights
Genetic analysis of hypertrophic cardiomyopathy (HCM) in Japanese patients revealed double heterozygous mutations in sarcomere genes. One identified double mutation was associated with earlier disease onset and increased severity.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Epidemiology
Background:
- Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder inherited in an autosomal-dominant pattern.
- Mutations in sarcomere genes are the primary cause of HCM, predominantly single heterozygous mutations.
- The clinical implications of multiple gene mutations in Japanese HCM patients remain unclear.
Purpose of the Study:
- To investigate the prevalence and clinical significance of multiple sarcomere gene mutations in Japanese patients with HCM.
- To identify specific mutations and their contribution to disease phenotype in a Japanese cohort.
Main Methods:
- Comprehensive genetic analysis of five key sarcomere genes (MYH7, MYBPC3, TNNT2, TPM1, TNNI3) in 93 unrelated Japanese patients.
- Identification and characterization of single and multiple heterozygous mutations.
- Family surveys and literature review to assess mutation pathogenicity and clinical correlation.
Main Results:
- Fourteen mutations were identified in 28 patients; 26 had single heterozygosity, while 2 had double heterozygosity.
- The identified double mutations were P106fs in MYBPC3 with R869C in MYH7, and R945fs in MYBPC3 with E1049D in MYH7.
- The proband with P106fs and R869C double mutation presented with earlier onset (28 years), greater wall thickness, and left ventricular outflow obstruction compared to relatives with single mutations.
Conclusions:
- A double mutation in sarcomere genes was identified in a Japanese cohort of HCM patients.
- The double mutation P106fs/R869C was associated with a more severe phenotype, including earlier onset and left ventricular outflow obstruction.
- Further research is necessary to elucidate the clinical significance of multiple mutations in HCM, particularly concerning phenotypic severity.
Background:
Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder with an autosomal-dominant pattern of inheritance mainly caused by single heterozygous mutations in sarcomere genes. Although multiple gene mutations have recently been reported in Western countries, clinical implications of multiple mutations in Japanese subjects are not clear.
Methods And Results:
A comprehensive genetic analysis of 5 sarcomere genes (cardiac β-myosin heavy chain gene [MYH7], cardiac myosin-binding protein C gene [MYBPC3], cardiac troponin T gene [TNNT2], α-tropomyosin gene [TPM1] and cardiac troponin I gene [TNNI3]) was performed in 93 unrelated patients and 14 mutations were identified in 28 patients. Twenty-six patients had single heterozygosity (20 in MYBPC3, 4 in MYH7, 1 in TNNT2, 1 in TNNI3), whereas 2 proband patients with familial HCM had double heterozygosity: 1 with P106fs in MYBPC3 and R869C in MYH7 and 1 with R945fs in MYBPC3 and E1049D in MYH7. From the results of the family survey and the previous literature on HCM mutations, P106fs, R945fs and R869C seemed to be pathological mutations and E1049D might be a rare polymorphism. The proband patient with P106fs and R869C double mutation was diagnosed as having HCM at an earlier age (28 years of age) than her relatives with single mutation, and had greater wall thickness with left ventricular outflow obstruction.
Conclusions:
One double mutation was identified in a Japanese cohort of HCM patients. Further studies are needed to clarify the clinical significance of multiple mutations including phenotypic severity.
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