下一代测序技术发现致心律失常性右室心肌病DSP基因新突变

发布时间：2018-05-26 20:48

  本文选题：致心律失常性右室心肌病 + 基因突变　； 参考：《浙江大学》2017年硕士论文

【摘要】：背景致心律失常性右室心肌病(arrhythmogenic right ventricular cardiomyopathy,ARVC)是一种遗传性心肌疾病,其基本病理特征为右室脂肪及纤维组织替代正常心肌组织。患者常于心肌结构及功能出现异常前发生室性心律失常和心源性猝死。目前认为本病的主要分子机制是桥粒功能缺陷损害心肌细胞电偶联,在近半数的ARVC患者中可以鉴定出5个主要的桥粒基因突变。然而相关基因或突变仍有待进一步研究。目的筛查1个心源性猝死家系的致病基因突变,旨在发现新的发病基因或基因突变,检测家系中的疾病基因携带者。方法回顾性分析了心源性猝死家系的先证者及其他成员临床资料,采集先证者外周血提取基因组DNA。首先应用高通量测序筛检先证者心源性猝死相关基因突变。采用Sanger测序验证可能与临床表型相关的基因变异。针对先证者基因检测结果,进一步对其他家系成员进行突变检测和临床分析。结果共有10名家系成员入选本研究。先证者基因检测发现2种新的基因突变,桥粒斑蛋白基因(DSP)第7号外显子的c.832delG杂合突变和A-激酶锚定蛋白9(AKAP9)第44号外显子的杂合错义突变。家系人员基因检测发现,6人具有和先证者相同的基因突变,其中2个携带DSP突变,2个携带AKAP9突变,2个均携带。应用不同的生物信息学预测软件发现DSP基因的移码突变可以改变翻译的阅读框,从而改变编码蛋白的氨基酸序列,被预测为具有致病性,而AKAP9的疾病相关性不明确。2名携带DSP突变的家系成员心脏磁共振检查结果符合ARVC的特征性表现。根据基因检测结果和临床情况,我们可以明确部分家系成员符合ARVC诊断。并结合文献进行了回顾和总结DSP基因突变和疾病表型的关系。结论本研究采集了心源性猝死家系临床资料,并通过基因检测,发现了新的DSP移码突变c.832delG,进一步阐明了 ARVC的分子遗传学机制以及对ARVC家系成员进行遗传检测和临床随访的必要性,可通过早期干预减少的疾病的危害,新发现的基因突变为ARVC的早期诊断和预测指标提供了新依据。
[Abstract]:Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary myocardial disease. Its basic pathological features are that right ventricular fat and fibrous tissue replace normal myocardial tissue. Ventricular arrhythmias and sudden cardiac death often occur before abnormal myocardial structure and function. It is believed that the main molecular mechanism of this disease is electrocoupling of cardiac myocytes with desmosome dysfunction. Five major desmosome gene mutations can be identified in nearly half of ARVC patients. However, the related genes or mutations still need to be further studied. Objective to screen the mutation of pathogenic gene in a family of sudden cardiac death (SCD) in order to find new pathogenic gene or gene mutation and detect the carriers of disease gene in the family. Methods the clinical data of the proband and other members of the pedigrees with sudden cardiac death were analyzed retrospectively, and the genomic DNAs were extracted from the peripheral blood of the proband. First, high-throughput sequencing was used to screen mutations in the proband's sudden cardiac death gene. Sanger sequencing was used to identify gene variations that might be associated with clinical phenotypes. The mutation and clinical analysis of other family members were carried out based on the results of proband gene detection. Results A total of 10 family members were selected in this study. Two new gene mutations, c.832delG heterozygosity in exon 7 and heterozygous missense mutation in exon 44 of A- kinase anchoring protein 9, were found in probands. Genetic analysis showed that 6 of them had the same gene mutation as the proband, including 2 with DSP mutation, 2 with AKAP9 mutation and 2 with AKAP9 mutation. Using different bioinformatics prediction software, it was found that the frameshift mutation of the DSP gene could change the translated reading frame, thus changing the amino acid sequence of the encoded protein, which was predicted to be pathogenicity. However, the disease correlation of AKAP9 was not clear. The results of cardiac magnetic resonance examination of 2 family members with DSP mutation were consistent with the characteristic features of ARVC. Based on the results of genetic tests and clinical conditions, we can confirm that some family members meet the ARVC diagnosis. The relationship between DSP gene mutation and disease phenotype was reviewed and summarized. Conclusion the clinical data of sudden cardiac death families were collected in this study. A new mutation of DSP frame shifter, c.832delG, was found. The molecular genetic mechanism of ARVC and the necessity of genetic detection and clinical follow-up of ARVC family members were further elucidated, which could be reduced by early intervention. The new gene mutation provides a new basis for early diagnosis and prediction of ARVC.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R542.2
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本文编号：1938842