Comprehensive Analysis Of The β-myosin Heavy Chain And Cardiac Myosin Binding Protein C Gene In Chinese Patients With Familial Hypertrophic Cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is a genetic disorder typically inherited in an autosomal dominant model,which is also showed chromosome recessive inheritance,X-chromosome links in some cases. About 50 percent of HCM patients exhibit an obvious familial aggregation. Besides,its high penetrance rises up with ages. Correlative studies demonstrated that HCM presented in 0.2% of general population. So, HCM is the most common genetic heart disease. In China,the recent two reports showed the disease phenotype for HCM was identified in 0.16% of subjects and the annual mortality rate was 1.6% or so. Clinical manifestations involve ventricular hypertrophy, especially ventricular septum asymmetric hypertrophy, cardiac arrhythmia, exercise intolerance and sudden death. Generally encoded cardiac sarcomere genes mutations are molecular mechanisms of HCM. About 15 encoding cardiac sarcomere genes whose mutations caused HCM have already been found. But two of the HCM-caused mutant gene predominated in frequency:β-myosin heavy chain gene (MYH7) and cardiac myosin-binding protein C gene (MYBPC3). They account for a proportion of disease-associated mutations which was consistently high in China, despite wide fluctuations attributable to the different genetic background. MYH7gene located on chromosome 14q11.2-q13,the gene consists of 40 exons and 38 of which encoding 1935 amino acids whereas its mRNA is 3 kb. Most of mutations take place on exon 3 to 26. By far, more than 80 SNPs have been found to cause the amino acid changes in the two regions: global head and head-rod junction of MYH7. MYBPC3 gene located on chromosome 11p11.2,the gene consists of 35 exons which encoding 1274 amino acids. Patients with mutations in MYBPC3 usually have a mild phenotype, delayed age of onset and favourable prognosis. Objective: This study was to reveal the disease-causing gene mutations in Chinese population with FHCM, and to analyze the correlation between the genotype and phenotype.Methods: We sequenced exons 13,15-16,26,and 27 of the MYBPC3 andexons 3-26 of the MYH7 gene in 6 families with HCM from the region of Anhui province in China.Genomic DNA was amplified, and fragments were directly sequenced. Each DNA variant found in the patients was also analyzed in 80 healthy controls through automatic sequencing.Results: Three different mutations (Arg723Gly and Ile736Thr in exon 20, Arg663His in exon 18)in MYH7 gene in three families and One mutation of Val896Met in two Chinese families with FHCM was detected. The mutation of Val896Met was reported for the first time in China. There was no obstruction in the left ventricular outflow tract in all patients. In five families, a total of 16 individuals were diagnosed HCM and 1 of them were healthy man. The DNA variant was not detected in 80 healthy controls.Conclusions: 1. The genes of MYH7 and MYBPC3 are most common sarcomeric genes involved in China families with HCM. 2. Exon 20 and 18 may be the frequent disease-causing exons in MYH7 gene in FHCM of Anhui area. 3. The mutation of V896M in MYBPC3 is a benign type. Moreover, the heart function of the people evidently more deteriorative when their age are more older. The mutation has been reported in the first in China.