Early expression of a malignant phenotype of familial hypertrophic cardiomyopathy associated with a Gly716Arg myosin heavy chain mutation in a Korean family

doi:10.1016/S0002-9149(98)00695-X

The American Journal of Cardiology

Volume 82, Issue 12, 15 December 1998, Pages 1509-1513

https://doi.org/10.1016/S0002-9149(98)00695-X Get rights and content

Abstract

The clinical course and prognosis of familial hypertrophic cardiomyopathy (HCM) are different according to the type of mutation in the genes for sarcomere proteins. It has been disputed that a mutation, which occurs at a functionally important region in the sarcomere proteins, may increase the penetrance and expressivity of the disease. We searched for a causative mutation in an HCM family, which is characterized by early expression of clinical phenotype, high incidence of sudden death at young ages, and progressive heart failure in adults. Among the 32 family members in 4 generations, 13 were affected; 4 died suddenly before age 16, 2 children have already had full expression of the cardiac hypertrophy, and other adults have either progressive heart failure or poor left ventricular systolic functions. PCR-SSCP (polymerase chain reaction–single strand confirmation polymorphism) analysis of genomic DNAs isolated from peripheral blood leukocytes of the family members identified a Gly716Arg mutation in the cardiac β-myosin heavy chain gene, which was cosegregated with the clinical phenotype. The mutation is localized near a functionally important site of the myosin heavy chain, the 2 active thiols, which contribute to the adenosine triphosphatase activity of myosin S1. This family provides further evidence that the mutation, which occurs at a functionally important site of the myosin heavy chain, is associated with the high penetrance and early expression of HCM.

Section snippets

Methods

The pedigree of a Korean HCM family (SM116 family), is shown in Figure 1. The family has 32 family members in 4 generations. After receiving consent, family members were screened by history, physical examination, electrocardiography, and 2-dimensional echocardiography. In addition, blood samples were obtained from each family members for DNA extraction.

Results

In the SM116 family, we looked at 32 family members in 4 generations (Figure 1). Thirteen of 32 family members were affected and 4 died suddenly in their early young ages. The clinical characteristics in 5 affected family members are listed in Table I.

Two-dimensional echocardiographic findings of the proband (II-10, 40 years old) showed that the left ventricle was enlarged (left ventricular end-diastolic dimension 60 mm, left ventricular end-systolic dimension 45 mm). Left ventricular global

Discussion

It is now well understood that familial HCM is a disease of the sarcomere. Linkage studies and candidate gene approaches have demonstrated that about half of the patients had mutations in 1 of 7 disease genes: cβMHC,1, 11 cardiac troponin T,12, 13 α-tropomyosin,13, 14 cardiac myosin-binding protein C,15, 16, 17 ventricular myosin essential light chain,18 ventricular myosin regulatory light chain,18 and cardiac troponin I.9 Other disease genes remain unknown.

In the analysis of HCM families with

Acknowledgements

We thank Jin-A Chu, RN (research nurse), for her contribution to family contact and blood sampling of the patients. We also thank Shitoshi Hiroi, MD, Tarshi Sasaoka, MD, Megumi Takahashi, MD, Tokeyuki Nokamura, MD, and Nobuhisa Ohbuch, MD, for their contributions in the screening of a mutation in HCM families.

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Cited by (32)

Mutation spectrum in a large cohort of unrelated chinese patients with hypertrophic cardiomyopathy
2013, American Journal of Cardiology
Citation Excerpt :
The malignant mutation (TNNT2-R92W) associated with a high risk of sudden death had a relatively high prevalence (1%) in our population compared with a low prevalence of this malignant mutations for Caucasions.16–18 Other common malignant mutations (R403Q, R453C, G716R, and R719W in MYH7) were not found in our study.17,19–21 No identified “hot spot” suggested the genetic heterogeneity of Han nationality.
Hypertrophic cardiomyopathy (HC) is a hereditary heterogeneous cardiovascular disorder. Existing data have been of predominantly Caucasian samples, and a large study is needed in Chinese population. The present study was intended to explore the genetic basis and clinical characteristics correlated with different genotypes in a large cohort of Chinese patients. Direct gene sequencing of β-myosin heavy chain (MYH7), myosin binding protein-C (MYBPC3), and cardiac troponin T (TNNT2) was performed in 136 unrelated Chinese HC patients. Clinical evaluations were conducted. In total, 32 mutations were identified in 36 patients (27%), including 10 novel ones. Distribution of mutations was 56% (MYBPC3), 31% (MYH7), and 13% (TNNT2), respectively. Double mutations were identified in 3% patients. The occurrence of HC-associated sarcomeric mutations was associated with an earlier age of onset, increased left ventricular hypertrophy, a higher incidence of syncope, previous family history, and sudden cardiac death. No statistical difference was identified in patients carrying MYBPC3 and MYH7 mutations with regard to clinical characteristics and outcomes. Patients with double mutations were associated with malignant progression in the study. In conclusion, MYBPC3 is the most predominant gene in HC. Multiple mutations are common in MYH7, MYBPC3, and TNNT2. The present study suggests a large diversity of HC and a prognostic role of genotype.
Sarcomeric genotyping in hypertrophic cardiomyopathy
2005, Mayo Clinic Proceedings
To pool results from studies of patients with hypertrophic cardiomyopathy (HCM) to elucidate important phenotypic differences among genotypes.
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).
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.
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.
Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy
2004, Journal of the American College of Cardiology
Citation Excerpt :
In searching for MYH7mutations, specific mutations previously ascribed as “malignant” or “benign” were identified. Three of 389 patients (<1%) had a “malignant” mutation: R403Q, R453C, and G716R (9,12,18–20). All three individuals were diagnosed with HCM at a young age (3 months, 16 years, and 24 years).
We sought to determine the prevalence and phenotype of beta-myosin heavy chain gene MYH7mutations in a large cohort of unrelated patients with hypertrophic cardiomyopathy (HCM).
Hypertrophic cardiomyopathy is a heterogeneous cardiac disease. MYH7mutations are one of the most common genetic causes of HCM and have been associated with severe hypertrophy, young age of diagnosis, and high risk of sudden cardiac death. However, these clinical findings from large, family studies have not been confirmed in a large unrelated cohort.
Deoxyribonucleic (DNA) samples obtained from 389 HCM outpatients seen at this tertiary referral center were analyzed for mutations, using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing for all 38 protein-coding exons of MYH7. Clinical data were extracted from patient records blinded to patient genotype.
Fifty-eight patients (15%) harbored 40 different mutations in MYH7. Compared with HCM patients without MYH7mutations, HCM patients with MYH7were younger at diagnosis (32.9 vs. 42.7 years, p = 0.0002), had more hypertrophy (left ventricular wall thickness of 24.2 vs. 21.1 mm, p = 0.0009), and more frequently underwent myectomy (60% vs. 38%, p = 0.002). The HCM patients with MYH7mutations more often had a family history of HCM (43% vs. 29%, p = 0.006), but there was no difference in family history of sudden death (16% vs. 14%, p = NS).
In this setting, HCM patients with MYH7were diagnosed at a younger age and had more hypertrophy, but they had no greater frequency of sudden death among first-degree relatives. Although these associations may prove useful for targeted gene screening, caution should be exercised in terms of using pathogenic status in risk stratification.
A novel missense mutation in the myosin binding protein-C gene is responsible for hypertrophic cardiomyopathy with left ventricular dysfunction and dilation in elderly patients
2003, Journal of the American College of Cardiology
Citation Excerpt :
We should screen patients diagnosed as having DCM for sarcomeric protein genes, including the cardiac MyBP-C gene. Some mutations in the beta-myosin heavy chain and the troponin T gene also have been reported to cause HCM with LV dysfunction (24–27). Kokado et al. (28)reported that a Lys183 deletion mutation in the troponin I gene in patients with HCM is associated with LV systolic dysfunction and dilation in those age >40 years.
We studied the clinical features of hypertrophic cardiomyopathy (HCM) caused by a novel mutation in the myosin binding protein-C (MyBP-C) gene in patients and family members of Japanese descent.
Previous reports have demonstrated that the clinical features of HCM associated with mutations in the MyBP-C gene include late onset and a favorable clinical course. Recently, some mutations in genes encoding sarcomeric proteins have been reported to be a cause of dilated cardiomyopathy (DCM), as well as HCM. However, mutations of the MyBP-C gene have not been reported as a cause of DCM up to now.
We analyzed MyBP-C gene mutations in 250 unrelated probands with HCM and in 90 with DCM. We used electrocardiography (ECG) and echocardiography to determine clinical phenotypes.
We identified 17 individuals in 8 families (7 HCM, 1 DCM) with an Arg820Gln mutation in the MyBP-C gene. Overall, 2 (40%) of 5 carriers age >70 years displayed “burnt-out” phase HCM, and one of them had been diagnosed as having DCM before genetic identification. The disease penetrance in subjects age >50 years was 70% by echocardiography and 100% by ECG, and that in those age <50 years was 40% and 50%, respectively.
Elderly patients with Arg820Gln mutation may show “burnt-out” phase HCM, and patients with this mutation may be included among those diagnosed as having DCM. Screening of patients with DCM, as well as HCM, for this mutation is of significant importance because patients with this mutation may be diagnosed clinically as having DCM.
Prevalence and age-dependence of malignant mutations in the beta-myosin heavy chain and troponin T genes in hypertrophic cardiomyopathy: A comprehensive outpatient perspective
2002, Journal of the American College of Cardiology
Citation Excerpt :
The life expectancy for individuals with R403Q (MHY7), R719W (MHY7) and R92W (TNNT2) mutations was 33 to 38 years old (17,23,25). The mean age at SCD was 30 years for both R453C and G716R (MHY73) mutations (19,24). Moreover, 95 individuals in our cohort had a positive family history of HCM, and 69 probands had family members who had died suddenly due to their HCM.
The goal of this study was to determine the prevalence of “malignant” mutations in hypertrophic cardiomyopathy (HCM).
Previous genotype-phenotype studies have implicated four mutations (R403Q, R453C, G716R and R719W) as highly malignant defects in the beta-myosin heavy chain (MYH7). In the cardiac troponin T gene (TNNT2), a specific mutation (R92W) has been associated with high risk of sudden death. Routine clinical screening for these malignant mutations has been suggested to identify high-risk individuals.
We screened 293 unrelated individuals with HCM seen at the Mayo Clinic in Rochester, Minnesota, between April 1997 and October 2000. Deoxyribonucleic acid (DNA) was obtained after informed consent; amplification of MYH7exons 13 (R403Q), 14 (R453C) and 19 (G716R and R719W), and TNNT2exon 9 (R92W) was performed by polymerase chain reaction. The mutations were detected using denaturing high-performance liquid chromatography and automated DNA sequencing.
The mean age at diagnosis was 42 years with 53 patients diagnosed before age 25. The mean maximal left ventricular wall thickness was 21 mm. Nearly one-third of cases were familial and one-fourth had a family history of sudden cardiac death. Only 3 of the 293 patients possessed one of the five “malignant” mutations, and all 3 patients were <25 years of age at presentation (p < 0.006).
This finding underscores the profound genetic heterogeneity in HCM. Only 1% of unrelated individuals seen at a tertiary referral center for HCM possessed one of the five “malignant” mutations that were examined. Routine clinical testing for these specific mutations is of low yield.
Different expressivity of a ventricular essential myosin light chain gene Ala57Gly mutation in familial hypertrophic cardiomyopathy
2001, American Heart Journal
Citation Excerpt :
The Met149Val mutation and Arg154His mutation in vMLC1 had 100% disease penetrance in subjects above the age of 18 years.7 We previously reported that a Gly716Arg mutation in β-MHC caused early expression of a malignant phenotype and complete disease penetrance.18 Clinical phenotypes caused by mutations in cMBPC and cTnT were characterized by low disease penetrance of familial HCM.10-13
Background Familial hypertrophic cardiomyopathy (HCM) is a clinically and genetically heterogeneous disease of the sarcomere. Molecular genetic studies have shown that familial HCM involves mutations in 8 different genes that encode proteins of the myofibrillar apparatus. Methods We thoroughly searched these genes to find the mutations in 38 probands of unrelated families with familial HCM. Results We found a novel missense mutation that resulted in Ala57Gly amino acid substitution of the ventricular essential myosin light chain (vMLC1) gene in two unrelated Korean families with familial HCM and one Japanese patient. The mutated site is located in the putative helix-loop-helix region (named EF-hand domain) of the calcium-binding site that is highly conserved in vMLC1 isoforms across the various species. The phenotype of this mutation in the affected families is a classic asymmetric septal hypertrophy, and the disease penetrance in genotyped members older than 18 years is 78%. In one Korean family a 42-year-old woman and two brothers (34 and 38 years old) with the mutation had fully expressed the disease, but two sisters (39 and 29 years old) with the mutation had no phenotypic expression of HCM. Conclusions Ala57Gly mutation in the vMLC1 gene may exhibit the classic form of familial HCM and widely different penetration of the disease phenotype in the family members with mutation, especially in women. (Am Heart J 2001;141:184-9.)

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^☆: This study was supported in part by grants from the Samsung Biomedical Research Institute (#SBRI C95-005-2) and the Korea Science and Engineering Foundation (KOSEF) to Dr. Park, and by grants from the Ministry of Health and Welfare, Japan, and the Japan Society for the Promotion of Science to A. Kimura.

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CardiomyopathyEarly expression of a malignant phenotype of familial hypertrophic cardiomyopathy associated with a Gly716Arg myosin heavy chain mutation in a Korean family☆

Abstract

Section snippets

Methods

Results

Discussion

Acknowledgements

Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1

N Engl J Med

A locus for familial hypertrophic cardiomyopathy is closely linked to the cardiac myosin heavy chain genes, CRI-L436, and CRI-L329 on chromosome 14 at q11–q12

Am J Hum Genet

Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy

N Engl J Med

Prognostic implications of novel β-cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy

J Clin Invest

Differences in clinical expression of hypertrophic cardiomyopathy associated with two distinct mutations in the β-myosin heavy chain gene

Circulation

Missense mutations in the β myosin heavy chain gene cause central core disease in hypertrophic cardiomyopathy

Proc Natl Acad Sci USA

Prognostic significance of β-myosin heavy chain mutations is reflective of their hypertrophic expressivity in patients with hypertrophic cardiomyopathy

J Investig Med

Complete sequence and organization of the human cardiac β-myosin heavy chain gene

Nucleic Acids Res

Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy

Nat Genet

Skeletal muscle expression and abnormal function of β-myosin in hypertrophic cardiomyopathy

J Clin Invest

A molecular basis for familial hypertrophic cardiomyopathya β cardiac myosin heavy chain gene missense mutation

Cell

Cardiomyopathy
Early expression of a malignant phenotype of familial hypertrophic cardiomyopathy associated with a Gly716Arg myosin heavy chain mutation in a Korean family☆