Autism spectrum disorder(ASD)is a neurodevelopmental disorder with high genetic heritability but heterogeneity.Fully understanding its genetics requires whole-genome sequencing(WGS),but the ASD studies utilizing WGS data in Chinese population are limited.In this study,we present a WGS study for 334 individuals,including 112 ASD patients and their non-ASD parents.We identified 146 de novo variants in coding regions in 85 cases and 60 inherited variants in coding regions.By integrating these variants with an association model,we identified 33 potential risk genes(P<0.001)enriched in neuron and regulation related biological process.Besides the well-known ASD genes(SCN2A,NF1,SHANK3,CHD8 etc.),several high confidence genes were highlighted by a series of functional analyses,including CTNND1,DGKZ,LRP1,DDN,ZNF483,NR4A2,SMAD6,INTS1,and MRPL12,with more supported evidence from GO enrichment,expression and network analysis.We also integrated RNA-seq data to analyze the effect of the variants on the gene expression and found 12 genes in the individuals with the related variants had relatively biased expression.We further presented the clinical phenotypes of the proband carrying the risk genes in both our samples and Caucasian samples to show the effect of the risk genes on phenotype.Regarding variants in noncoding regions,a total of 74 de novo variants and 30 inherited variants were predicted as pathogenic with high confidence,which were mapped to specific genes or regulatory features.The number of de novo variants found in patient was significantly associated with the parents’ages at the birth of the child,and gender with trend.We also identified small de novo structural variants in ASD trios.The results in this study provided important evidence for understanding the genetic mechanism of ASD.
目的:在中国人非综合征型唇裂伴或不伴腭裂(non-syndromic cleft lip with or without palate,NSCL/P)核心家系中,利用全外显子组测序探索与NSCL/P发病相关的新生突变位点。方法:对22个中国NSCL/P核心家系进行全外显子组测序,采用基因组分析工具包(Genome Analysis ToolKit,GATK)通过对比亲代与子代同一位点的等位基因识别新生突变位点,采用SnpEff软件对位点进行功能注释。对新生突变位点进行富集分析,检验全外显子区域内存在的新生突变数量是否高于预期值,以及是否存在包含新生突变数量显著高于预期值的基因。通过查阅文献总结既往研究提示与NSCL/P发病存在较强证据支持的基因,根据注释信息筛选能够引起蛋白质改变的新生突变位点,对该类位点所在基因编码的蛋白质与NSCL/P相关基因编码的蛋白质进行交互作用分析。利用R软件的denovolyzeR包进行富集分析(Bonferroni多重检验校正:P=0.05/n,n为基因个数)。利用STRING数据库预测新生突变所在基因与已知NSCL/P致病基因编码的蛋白质间的交互作用。结果:全外显子组测序得到的位点中共有339908个位点通过质量控制,经GATK软件比对共筛选出345个高置信度新生突变,其中错义突变44个,无义突变1个,经典剪接位点2个,同义突变20个,内含子区或基因间区位点278个。富集分析显示,全外显子组中引起蛋白质改变的新生突变数量显著高于预期值(P<0.05),KRTCAP2、HMCN2、ANKRD36C、ADGRL2和DIPK2A 5个基因所含的新生突变位点高于预期(P<0.05/(2×19618))。蛋白质交互作用分析纳入46个包含能够引起蛋白质序列改变的新生突变所在的基因及13个既往研究提示与NSCL/P存在关联的基因,两类基因编码的蛋白质之间存在6组交互作用,其中RGPD4与SUMO1编码的蛋白质的交互作用证据可信度最高,STRING数据库交互作用评分为0.868。结论:研究为NSCL/P的发病提供了新的证据,对携
目的:比较使用口内扫描法和传统硅橡胶法制取种植磨牙单冠的临床修复效果评价。方法:选择62例患者(共86颗后牙),随机分为试验组和对照组,每组43颗牙(其中前磨牙13颗,磨牙30颗)。临床分别采用硅橡胶法和口内扫描法制取印模,制作氧化锆全瓷修复体,于治疗后2周复诊,采用VAS评分量表及改良的美国公共卫生总署(United states public health service,USPHS)评价系统对修复效果及舒适度进行评价。结果:口内扫描法组的患者满意度更高,舒适度更好,两组USPHS评分中除口内扫描组修复体的边缘适合性A级比例比对照组高外,其余指标的A级比例差异无统计学意义(P>0.05)。结论:口内扫描技术应用在种植磨牙单冠的印模制作中,修复效果良好、精度高外,患者满意度高,值得临床推广应用。
