Mutations profile in Chinese patients with hypertrophic cardiomyopathy
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.
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Cited by (59)
Effect of Cis-Compound Variants in MYH7 on Hypertrophic Cardiomyopathy With a Mild Phenotype
2022, American Journal of CardiologyCitation Excerpt :After excluding polymorphisms and neutral variants, 3 rare variants that changed amino acid coding were identified (Table 1). According to the current guidelines of the American College of Medical Genetics,12 the c.4258C>T (p.Arg1420Trp) variant within Exons 31 of the MYH7 gene was reported previously in familial HC and classified as likely pathogenic.13,14 The c.2465T>C (p.Met822Thr) variant in the MYH7 gene and the c.55885C>T (p.Arg18629Cys) variant in the TTN gene were variants of undetermined significance (VUS).
Whole-exome sequencing identifies rare compound heterozygous mutations in the MYBPC3 gene associated with severe familial hypertrophic cardiomyopathy
2018, European Journal of Medical GeneticsCitation Excerpt :The mutation, c.772G > A (pGlu258Lys), was previously identified as one of the most prevalent variants associated with HCM. It is associated with a replacement of the amino acid lysine with glutamic acid at position 258 in the cMyBP-C protein (Ehlermann et al., 2008; Nanni et al., 2003; Niimura et al., 1998; Olivotto et al., 2008; Page et al., 2012; Richard et al., 2003; Song et al., 2005; Van Driest et al., 2004). Identification of the c.659A > G (p.Tyr220Cys) mutation was novel.
Significance of intronic and synonymous MYBPC3 gene variations in hypertrophic cardiomyopathy
2017, Gene ReportsCitation Excerpt :This SNP could contribute to the phenotype along with the influence of other intrinsic/extrinsic environmental factors/modifier genes on the disease phenotype. Exon 26 revealed c.2547C > T resulting in a synonymous variation (pVal849Val) (rs3729953), previously reported in a Chinese population (Song et al., 2005), belonging to the fibronectin type III domain with predominance of genotypic frequency (31%) in the patient group compared to 21% in the controls. In-silico analysis predicted a shift of the binding site for SF2/ASF protein along with the disruption of the enhancer binding site and simultaneous creation of a cryptic silencer site for hnRNP A1.
Cardiac troponin structure-function and the influence of hypertrophic cardiomyopathy associated mutations on modulation of contractility
2016, Archives of Biochemistry and BiophysicsCitation Excerpt :Since the first mutations associated with HCM were detected in 1993 [10,20], there has been a dramatic increase in the number of cTn mutations reported. Thus far, a total of at least 69 mutations have been identified in cTn subunit proteins that have been reported to be associated with HCM, including 6 in cTnC (Fig. 2A) [19,126,127], 29 in cTnI (Fig. 2B) [5,16,128–137], and 34 in cTnT (Fig. 2C) [9,15,129,137–143]. All of the mutations are single nucleotide polymorphisms (SNPs or variants), and the degree of cardiac pathology associated with them is highly variable as is verification of their causal nature.
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Both authors contribute equally to the work.