小耳畸形染色体大片段变异及相关基因研究-整形外科学专业论文.docx

中国医学科学院北京协和医学院博士研究生学位论文研究结果1．先天性小耳畸形患者组共发现染色体大片段变异5例，对照组没有发现阳性 结果。对染色体变异在先天性小耳畸形患者和对照组中出现的频率进行确切概率 法检验，P=0．0033，表明该差异具有统计学意义。2．其中2例表现为染色体结构变异：病例一为13号、14号染色体长臂部分重 复，14号染色体断裂片段内发现同源框基因OTX2,OTX2-ASl，对拷贝数增加的染 色体片段进行基因筛选，发现2个与NCC及耳发育相关基因及信号通路基因： BMP4及GSC；病例二为5号染色体长臂部分重复，染色体断裂片段内未发现小耳 畸形相关的基因，对拷贝数增加的片段内进行检索，发现FGF信号通路相关基因阳F，粥职t FGFl和BMP信号通路相关基因耶Z MSX2,SMAD5。3．另外3例表现为染色体数目变异：均表现为X染色体增加。其中一例为XXY综合征；另外两例为X三体综合征。研究结论1．对染色体变异在先天性小耳畸形患者和对照组中出现的频率进行确切概率 法检验，显示先天性小耳畸形患者中出现染色体变异的频率高于正常对照，说明 染色体变异与先天性小耳畸形的发生存在一定的相关性。2．14号染色体发生畸变的位置累及基因OTX2，可能与该病例小耳畸形的发病 有关。3．13、14号染色体重复导致GSC、BMP4基因拷贝数增加，可能与小耳畸形发生有关。4．5号染色体长臂部分重复导致FGF信号通路相关基因FGFl8,FGFR4,FGFl 和BMP信号通路相关基因FST,MSX2,SMAD5拷贝数增加，可能与小耳畸形发病 有关。关键词：小耳畸形，拷贝数分析，染色体变异，致病基因2万方数据Microtia associated large fragment chromosome variations and relevant genesAbstractBackgroundMicrotia，which encompasses a spectrum of congenital anomalies of the externaland middle ear，involves immature derivatives from the first and second pharyngeal arches．The pathogenesis of microtia is perplexing．Environmental factor such as retinoic acid has been proved to be associated in microtia pathogenesis．Significant geneticcontribution is confirmed：(1)Higher concordance in monozygotic twins than indizygotic twins；(2)Incomplete penetrance and variable expression has been observed in family cases；(3)Family cases ranging from 3 to 34％；(4)Chromosomal aberrations or single—gene defects have been reported；5)Mutations of specific genes result in microtiain mice．Therefor research on genetic mutation site is of great importance to illuminatepathogenesis of microtia．objeetiveGenetic disorders associated、杭也microtia was subgrouped into alterations at chromosomal level and gene level．We conduct copy number analysis using the genotype data from the genome-wide SNP array among microtia patients for chromosomalmalformations．Furthermore，the neighbouring genes of chromosomal aberrations or genes in the extra or deleted chromosome fragments would be screened to investigate the possible causative