先天性小耳畸形染色体变异及相关基因的研究  

Microtia associated large fragment chromosome variations and relevant genes

作　　者：王冰清 程琳 陈琪 钱瑾 张娇 张永彪 章庆国 Wang Bingqing;Cheng Lin;Chen Qi;Qian Jin;Zhang Jiao;Zhang Yongbiao;Zhang Qingguo(Department of Ear Reconstruction,Plastic Surgery Hospital,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100144,China)

机构地区：[1]中国医学科学院北京协和医学院整形外科医院外耳再造中心,100144

出　　处：《中华整形外科杂志》2020年第5期515-522,共8页Chinese Journal of Plastic Surgery

基　　金：国家自然科学基金(81372085,81571924,81701930)。

摘　　要：目的在全基因组范围内筛选可能与先天性小耳畸形有关的染色体大片段变异及相关致病基因。方法根据入选标准从2012年1月至2014年1月就诊于中国医学科学院整形外科医院的先天性小耳畸形患者中选择病例组,以同时期内在同一医院行常规整形美容手术治疗的、不患有任何先天性遗传病、年龄相近的正常人群为对照组。采集2组患者的静脉血,提取基因组DNA,并运用基因芯片技术及相关软件对2组病例的染色体进行拷贝数变化(CNV)分析,明确染色体变异的类型,定位畸变发生的位置及受影响的染色体片段长度,并通过等位基因频率的比较,得到因染色体变化发生改变的基因,从中筛查出与先天性小耳畸形发生相关的致病基因。采用Fisher确切法检验进行统计学分析,以P<0.05为差异有统计学意义。结果病例组共纳入942例先天性小耳畸形患者,男695例,女247例,年龄(11.4±3.2)岁;对照组1802例,男1290例,女512例,年龄(11.6±4.9)岁。病例组共发现染色体大片段变异5例,对照组未见染色体异常,2组比较差异具有统计学意义(P=0.003)。染色体变异的5例中,染色体数目变异3例,其中1例为XXY综合征,另外2例为X三体综合征;染色体结构变异2例,其中1例为13号、14号染色体长臂部分重复,发现了可能与小耳畸形相关的基因:OTX2、BMP4和GSC,另1例为5号染色体长臂部分重复,发现FGF信号通路相关基因FGF18、FGFR4、FGF1和BMP信号通路相关基因FST、MSX2、SMAD5。结论染色体变异与先天性小耳畸形的发生存在一定的相关性;通过筛查发现可能有10个相关的基因通过各种不同的途径参与了小耳畸形的发生。Objective To find the chromosomal malfomations among microtia patients and the neighbouring genes of chromosomal aberrations or genes in the extra or deleted chromosome fragments would be screened to investigate the possible causative genes.Methods According to the inclusion criteria,case group was selected from microtia patients referred to Plastic Surgery Hospital,Chinese Academy of Medical Science,between January 2012 and January 2014,and the control group was the normal people of similar age received plastic surgery in the same hospital in the same time who did not have any congenital genetic disease.Blood samples of two groups were collected,and genomic DNA was extracted,then copy number variation(CNV)analysis was performed in the two groups with gene chip technology and associated software for large fragment chromosomal malformations.The variations of chromosome copy number were recorded to further analyze the type and length of chromosome structure variation.The genes at the loci of break points were further screened referring to B allele frequency to interpret associated genes related to the occurrence of microtia.Fisher exact test were used for statistical analysis,and the difference was statistically significant(P<0.05).Results 942 patients with congenital microtia were included in the case group,695 males and 247 females,aged(11.4±3.2)years;1802 normal controls,1290 males and 512 females,aged(11.6±4.9)years.Large chromosomal fragments variations were detected in 5 patients in chromosome in case group(P=0.003).The difference between the two groups was statistically significant(P=0.003).Three cases were found to carry an extra X chromosome.Among the 3 cases,one patient suffered from XXY karyotype and the other 2 patients X trisomy.Two cases were proved to be associated with chromosome structural variations.The malformations of the first case presented partial duplication of the long arm of chromosome 13 and 14.On searching for causative genes,OTX2,BMP4 and GSC were detected to be in the chromosome stru

关 键 词：先天性小耳畸形 染色体变异 拷贝数变化 三体 

分 类 号：R764.7[医药卫生—耳鼻咽喉科]