本文選題：致心律失常性右室心肌病 + 基因突變　； 參考：《浙江大學(xué)》2017年碩士論文

【摘要】：背景致心律失常性右室心肌病(arrhythmogenic right ventricular cardiomyopathy,ARVC)是一種遺傳性心肌疾病,其基本病理特征為右室脂肪及纖維組織替代正常心肌組織�；颊叱Ｓ谛募〗Y(jié)構(gòu)及功能出現(xiàn)異常前發(fā)生室性心律失常和心源性猝死。目前認(rèn)為本病的主要分子機制是橋粒功能缺陷損害心肌細(xì)胞電偶聯(lián),在近半數(shù)的ARVC患者中可以鑒定出5個主要的橋�；蛲蛔�。然而相關(guān)基因或突變?nèi)杂写M(jìn)一步研究。目的篩查1個心源性猝死家系的致病基因突變,旨在發(fā)現(xiàn)新的發(fā)病基因或基因突變,檢測家系中的疾病基因攜帶者。方法回顧性分析了心源性猝死家系的先證者及其他成員臨床資料,采集先證者外周血提取基因組DNA。首先應(yīng)用高通量測序篩檢先證者心源性猝死相關(guān)基因突變。采用Sanger測序驗證可能與臨床表型相關(guān)的基因變異。針對先證者基因檢測結(jié)果,進(jìn)一步對其他家系成員進(jìn)行突變檢測和臨床分析。結(jié)果共有10名家系成員入選本研究。先證者基因檢測發(fā)現(xiàn)2種新的基因突變,橋粒斑蛋白基因(DSP)第7號外顯子的c.832delG雜合突變和A-激酶錨定蛋白9(AKAP9)第44號外顯子的雜合錯義突變。家系人員基因檢測發(fā)現(xiàn),6人具有和先證者相同的基因突變,其中2個攜帶DSP突變,2個攜帶AKAP9突變,2個均攜帶。應(yīng)用不同的生物信息學(xué)預(yù)測軟件發(fā)現(xiàn)DSP基因的移碼突變可以改變翻譯的閱讀框,從而改變編碼蛋白的氨基酸序列,被預(yù)測為具有致病性,而AKAP9的疾病相關(guān)性不明確。2名攜帶DSP突變的家系成員心臟磁共振檢查結(jié)果符合ARVC的特征性表現(xiàn)。根據(jù)基因檢測結(jié)果和臨床情況,我們可以明確部分家系成員符合ARVC診斷。并結(jié)合文獻(xiàn)進(jìn)行了回顧和總結(jié)DSP基因突變和疾病表型的關(guān)系。結(jié)論本研究采集了心源性猝死家系臨床資料,并通過基因檢測,發(fā)現(xiàn)了新的DSP移碼突變c.832delG,進(jìn)一步闡明了 ARVC的分子遺傳學(xué)機制以及對ARVC家系成員進(jìn)行遺傳檢測和臨床隨訪的必要性,可通過早期干預(yù)減少的疾病的危害,新發(fā)現(xiàn)的基因突變?yōu)锳RVC的早期診斷和預(yù)測指標(biāo)提供了新依據(jù)。
[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.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R542.2
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本文編號：1938842