家族性肥厚型心肌病致病基因的临床研究

发布时间：2018-04-14 03:06

本文选题：心肌病 + 肥厚型　；参考：《郑州大学》2017年硕士论文

【摘要】：背景肥厚型心肌病(HCM)是最常见的遗传性心脏病,具有显著的遗传异质性。对HCM的认识已逾50年,最近在HCM诊断和治疗方面取得了实质性的进展,临床实践中对本病的认识也随之提高。目前已发现至少27个HCM致病基因,超过1500个突变与HCM相关。国内对HCM的致病基因的研究多局限于数个编码肌小节的基因,这必然导致致病基因的检出率降低,使一部分携带其他致病基因HCM病例筛查不出致病基因,对其家系成员的筛查及遗传学研究也就无从谈起。目的利用新一代高通量测序技术(NGS)对人心肌病相关的靶基因组的44个基因全测序,并分析基因突变的特点以及基因型及临床表型的关系。方法纳入2012-2016年就诊于河南省胸科医院的家族性肥厚型心肌病(FHCM)先证者15名,搜集临床资料(包括病史、体格检查、心脏彩超、心电图),全面筛查44个人泛心肌病靶基因。对基因筛查阳性的先证者,应用Sanger测序检测家系中其他成员的特定基因。对新发现的突变基因,通过Poly Phen-HCM及不同物种的蛋白序同源性对比确定其致病性,并与健康对照组进行对比,最后对致病性突变携带者进行基因型及临床表型相关性的分析。结果入组的15名肥厚型心肌病先证者中,在8位先证者发现了HCM 5个相关致病基因的9种突变,其中1例为双基因突变,2例为新发现的突变,国内外均未见报道。结论1.MYBPC3基因9号外显子c.903del G突变以及MYBPC3基因26号外显子c.2834GA突变国内外均未见报道,为新发现的致病性突变。MYBPC3基因c.903del G突变临床表型严重,易于发生恶性心率失常,治疗上需要采取更积极的措施;MYBPC3基因26号外显子c.2834GA突变临床表型具有多样性。2.在家系遗传的基础上可以发生从头突变,双突变携带者发病早,心肌肥厚程度重,临床表现较重,预后较差。
[Abstract]:Background HCM (hypertrophic cardiomyopathy) is the most common hereditary heart disease with significant genetic heterogeneity.HCM has been recognized for more than 50 years. Recently, substantial progress has been made in the diagnosis and treatment of HCM, and the understanding of the disease has also been improved in clinical practice.At least 27 HCM genes have been identified and more than 1500 mutations are associated with HCM.Most of the studies on the pathogenicity genes of HCM in China are limited to several genes that encode muscle sections, which will inevitably lead to a decrease in the detection rate of pathogenic genes, which makes some HCM cases carrying other pathogenic genes fail to screen out the pathogenic genes.Screening and genetic research for members of their families are also out of the question.Objective to complete the sequencing of 44 genes in human cardiomyopathy related target genomes using a new generation of high-throughput sequencing technique (NGS), and to analyze the characteristics of gene mutation and the relationship between genotype and clinical phenotype.Methods Fifteen patients with familial hypertrophic cardiomyopathy (FHCM) who were admitted to Henan chest Hospital from 2012 to 2016 were enrolled. Clinical data (including medical history, physical examination, echocardiography, electrocardiogram) were collected and 44 pancardiomyopathy target genes were screened.Sanger sequencing was used to detect the specific genes of other members of the family.The pathogenicity of the newly discovered mutant gene was determined by the homology of Poly Phen-HCM and the protein sequence of different species, and compared with that of the healthy control group. Finally, the relationship between genotype and clinical phenotype of the mutant carriers was analyzed.Results among the 15 probands of hypertrophic cardiomyopathy, 9 mutations of 5 pathogenetic genes related to HCM were found in 8 probands, of which 1 case was a double gene mutation and 2 cases were newly discovered mutations, which have not been reported at home and abroad.Conclusion c.903del G mutation in exon 9 of 1.MYBPC3 gene and c.2834GA mutation in exon 26 of MYBPC3 gene have not been reported at home and abroad. It is a new pathogenicity mutation. C.903del G mutation of MYBPC3 gene has serious clinical phenotype and is prone to malignant heart rate disorder.The clinical phenotype diversity of c.2834GA mutation in exon 26 of MYBPC3 gene needs to be more active.On the basis of genetic inheritance at home, AB _ o mutation can occur. Double mutation carriers have early onset, heavy myocardial hypertrophy, severe clinical manifestations and poor prognosis.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R542.2

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