基因检测联合多模态影像技术对宁夏回族人群肥厚型心肌病早期诊断及基因型-临床表型关联性研究

The occurrence and development of hypertrophic cardiomyopathy (HCM ) are the results of joint action of gene mutation and other external multiple factors. In other words, HCM not only caused by gene mutation , the dominant factor, but other external factors can also contribute to it. The severe condition of HCM can directly lead to sudden cardiac death. Therefore, it is of great significance not only to make the preclinical diagnosis for HCM; as well, to reveal the correlation between genotype and clinical phenotype of HCM. By now, there were no relevant reports and data found about HCM in Chinese Hui nationality .. The results from our previous studies for 83 HCM families of Chinese Han nationality showed that after detecting by target exome capture and high-throughput sequencing technique and detecting by the following three medical imaging technologies which were conventional two-dimensional transthoracic echocardiography (2D-TTE), three-dimensional speckle tracking echocardiography (3D-STE) and cardiac magnetic resonance imaging(CMRI). Six gene mutations were found that there were respectively MYBPC3-P1208fs, ANK2-H556R, MYBPC3-E334K, ABCC1-P371fs, TTN-P60079fs and ANK2-P1974H; segmental myocardial strain significantly reduced with fibrosis; MYBPC3 gene P1208fs mutation could lead to HCM and ANK2 gene H556R mutation might not be pathogenic; The global myocardial strain was more significantly reduced in MYBPC3 truncated mutations than that in missense mutations.. The hypothesis of this study is that there are most probably some differences both in genotype and in clinical phenotype of HCM between Chinese Hui nationality and Chinese Han nationality . . In this study, we will use target exome capture and high-throughput sequencing technique combined with above three kinds of medical imaging technologies (2D-TTE, 3D-STE and CMRI) and another newly developed technology Vector Flow Mapping(VFM ) to carry out gene detection and to measure some medical imaging parameters in patients with HCM in Ningxia Hui nationality. As a result, it is capable of making preclinical diagnosis for HCM and of revealing the correlation between genotype and clinical phenotype of HCM. The final aim of this study is to minimize the mortality rate and the occurrence of sudden cardiac death.

肥厚型心肌病（HCM）的发生发展是基因突变和其它外界多重因素共同作用的结果，严重者发生心源性猝死。故早期诊断并揭示基因型与临床表型的关联性临床意义重大。目前尚未见中国回族人群HCM相关内容的报道。前期研究对中国汉族人群83个HCM家系应用外显子高通量测序及常规2D-TTE、3D-STE和CMRI检测发现MYBPC3-P1208fs和ANK2-H556R 等6个突变位点；早期节段心肌应变减低和纤维化；MYBPC3基因P1208fs突变导致HCM而ANK2基因H556R可能不具致病性；MYBPC3截短突变较错义突变整体应变明显减低。 .本课题假设：中国回族人群与汉族人群HCM基因型与临床表型可能均存在差异。本课题应用外显子高通量测序联合上述三种影像技术及VFM拟对宁夏回族人群HCM进行基因检测和影像学指标检测，早期诊断并揭示基因型与临床表型的关联性，旨在最大限度降低患者死亡率和心源性猝死发生。

肥厚型心肌病（HCM）是一种常见的心肌肌小节蛋白基因突变导致的常染色体显性遗传病。基因检测是诊断HCM的金标准；常规二维经胸超声心动图（2D-TTE）可以诊断 HCM 并可提供其心脏的形态学特征、血流动力学特征和心室收缩及舒张功能信息；三维斑点追踪超声心动图（3D-STE）可早期评估心肌节段及整体运动；心脏磁共振成像技术（CMRI）可定量观察和测量心室壁肥厚程度以及纤维化情况。本项目应用外显子高通量测序联合上述三种影像技术对宁夏回族人群HCM进行检测发现导致一回族家系FHCM的罕见致病基因TTN及突变位点Val135643Ile；2D-TTE联合3D-STE建立数学模型可以显著提高识别HCM中MYH7突变基因携带者的诊断效率，并且左室后壁厚度（LVPWT）最大值可以作为区分MYH7G+P-与MYBPC3G+P-的独立预测指标；3D-STE能够敏感识别出无症状致病基因携带者早期左室整体及局部收缩功能的异常；HCM致病基因携带者整体及部分节段出现纵向应变减低且TLS-diff%明显延长，提示在室壁尚未发生肥厚时，心室纵向收缩不同步现象已发生，对于HCM患者及其家系中的致病基因携带者而言，可将左室壁最大厚度（LVMWT）与3D-STE不同步性指标联合应用，作为指导临床治疗方案制定及疗效评价的客观依据。.本研究应用基因检测联合多模态影响技术对宁夏回族人群HCM进行基因检测和影像学指标检测，早期诊断并揭示了基因型与临床表型的关联性，为最大限度降低患者死亡率和心源性猝死发生提供了理论基础。

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