Mutations profile in Chinese patients with hypertrophic cardiomyopathy

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Abstract

Background

There are more than 1 million patients with hypertrophic cardiomyopathy (HCM) in China, but the genetic basis is presently unknown.

Methods

We investigated 100 independent patients with HCM (proband 51, sporadic 49) by sequencing the three most frequent HCM-causing genes (MYH7, MYBPC3, TNNT2).

Results

Thirty-four patients (34%) carried 25 types of mutations in the selected genes, most (14/25) were newly identified. MYH7 and MYBPC3 accounted for 41% and 18% of the familial HCM, respectively. TNNT2 mutations only caused 2% of the familial HCM. These results suggested that MYH7 and MYBPC3 were the predominant genes responsible for HCM, and TNNT2 mutation less proportionally contributed to Chinese HCM. MYH7 mutations caused HCM at younger age, more frequent syncope and ECG abnormalities compared with MYBPC3 mutations. The patients carrying R663C, Q734P, E930K in MYH7 and R130C in TNNT2 expressed malignant phenotype. R403Q in MYH7, the most common hot and malignant mutation in Caucasians, was not identified in Chinese.

Conclusion

We confirmed the diversity of mutation profile in different populations and suggest that a global registry of HCM mutations and their phenotypes is necessary to correlate genotype with phenotype.

Introduction

Hypertrophic cardiomyopathy (HCM) is characterized by left and/or right ventricular hypertrophy, with predominant involvement of the interventricular septum in the absence of other causes of hypertrophy, such as hypertension or valvular heart disease. It has been reported that at least 13 genes were implicated in 60–70% of HCM. The most common genes are cardiac β-myosin heavy chain gene (MYH7), cardiac troponin T gene (TNNT2) and cardiac myosin-binding protein C gene (MYBPC3), accounting for approximately 30–50%, 20–25% and 20% of familial HCM, respectively. It has been estimated that the mutations in the three genes contribute to around three-quarters of HCM [1], [2], [3]. However, intra- and interfamilial variations have been noticed in the penetrance, the degree of hypertrophy and the risk of sudden death even carrying the identical mutation. Factors accounting for the significant variability are probably related to either distinct mutated genes or different mutations within a given gene, or interaction between disease-causing gene and modifier gene and/or environmental factors [4], [5].

To date, most data on HCM were derived from studies in Caucasians, which show that MYH7 was the predominant HCM-causing gene. But recent studies indicated that MYBPC3 was the most common HCM-causing genes in eastern Finland and northern Sweden [6], [7]. Little is known about the genetic basis of Chinese patients with HCM. Because of the heterogeneity in genetic background between Chinese and Caucasians [8], [9], we hypothesized that the gene mutation profile may be distributed differently in Chinese. There are at least 1 million of patients with HCM in China [10].

Section snippets

Subjects recruitment

All patients were recruited from the cardiovascular clinic at Beijing Fuwai Hospital from the year 1997 to 2001. One hundred unrelated patients (51 probands and 49 sporadic cases) and 120 unrelated age- and sex-matched normal controls were enrolled in the study. None of the control subjects had a history of serious systemic diseases. Three hundred and fifty-six familial members also underwent clinical and genetic evaluations from 25 of the 51 HCM pedigrees. The study protocol was reviewed and

Genetic study

Of the 100 patients with HCM, 34 (34%) were carriers for gene mutations in the selected genes (MYH7, MYBPC3, TNNT2). In familial HCM, 61% (31/51) of the probands had mutations and 6% (3/49) in the sporadic cases. The location and frequency of the gene mutations were recorded in Table 1. In this study, MYH7, MYBPC3 and TNNT2 accounted for approximately 41%, 18% and 2% of familial HCM, respectively.

A total 25 kind of mutations were found in this study, 14 were novel and 3 were de novo (MYH7:

Discussion

To date, at least 270 mutations responsible for HCM were identified (http://genetics.med.harvard.edu/~seidman/cg3/index.html). In our investigation, 25 mutations were identified in 34 patients from the three common HCM-causing genes. This study provided further evidence that mutations in the MYH7 gene (41%, 21/51) are the most common cause of familial HCM in Chinese as well. The second most common gene responsible for Chinese HCM appears to be the MYBPC3 gene (18%, 9/51). TNNT2 has been

Acknowledgement

The study was supported (grant to Rutai Hui) by the Ministry of Science and Technology, and Beijing Municipal Commission of Science and Technology.

References (30)

  • B.J. Maron et al.

    Task Force on Clinical Expert Consensus Documents. American College of Cardiology; Committee for Practice Guidelines. European Society of Cardiology. American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines

    J. Am. Coll. Cardiol.

    (2003)
  • K.R. Chien

    Genotype, phenotype: upstairs, downstairs in the family of cardiomyopathies

    J. Clin. Invest.

    (2003)
  • M. Lechin et al.

    Angiotensin-I converting enzyme genotypes and left ventricular hypertrophy in patients with hypertrophic cardiomyopathy

    Circulation

    (1995)
  • A.P. Osterop et al.

    AT1 receptor A/C1166 polymorphism contributes to cardiac hypertrophy in subjects with hypertrophic cardiomyopathy

    Hypertension

    (1998)
  • P. Jaaskelainen et al.

    Mutations in the cardiac myosin-binding protein C gene are the predominant cause of familial hypertrophic cardiomyopathy in eastern Finland

    J. Mol. Med.

    (2002)
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