家系分析先天性心脏病基因组新生突变及相关谱系的构建

Congenital heart disease (CHD) is the birth defect with the highest incidence of neonatal diseases. The pathogenesis CHD is not clear, and there is no accurate genes for screening target. In the previous study, 32 CHD trios and 361 sporadic cases were collected and whole exom from 20 trios samples were sequenced by next generation sequencing (NGS). 43 de novo mutations (DNM) were identified compared with probands’ nomal genotypes by integtated bioinformatic methods, basing on genomic sequences of different populations in China. Functional enrichment analysis revealed a significant correlation with cardiac development. According to the results, the analysis plan of "accurate analysis of genetic variation of CHD trios based on population genomes" was proposed. Therefore, in the present study, more samples will be collected, and NGS will also be used to obtain DNMs. bioinformatics analysis will perform to assess genetic risk and get functional enrichment on the mutations, and thus to construct panels of genetic variations associated with CHD, which were confirmed on clinical samples and cells. This study can provide diagnostic targets for prenatal gene screening and provide evidence for mechanism research of CHD.

先天性心脏病（简称先心病），是新生儿发生率最高的出生缺陷，病因复杂，发病机制尚不明确，缺乏有效的产前基因筛查靶点。课题组前期建立了32个先心病家系和361个散发病例的样本库，通过下一代测序技术对其中20个家系进行了全外显子组测序，并以中国人类遗传资源库各民族基因组信息为背景，结合家系中正常父母基因型，设计了新的生物信息学分析方法，发现了43个基因携带有44个新生突变，功能富集分析发现与心脏发育显著相关。因此提出了“以民族基因组为背景精准分析先心病家系遗传变异”的分析方案。本研究拟在此基础上，综合样本库中收录的家系和大样本散发病例，生物信息学对变异位点进行遗传风险评估及功能富集分析，构建先心病相关基因变异谱系（panel），并在临床样本及细胞学实验中对谱系进行功能验证。本研究可为先心病孕早期产前基因筛查提供参照靶点，同时为研究先心病发病遗传机制的提供依据。

先天性心脏病（简称先心病，CHD）是我国最主要的出生缺陷类型，常导致流产、死胎等，给社会及家庭带来沉重负担。但是由于先心病的病因复杂，目前其具体发病机制尚不完全明确，缺乏有效的产前诊断筛查的基因靶点。在课题组前期研究基础上，本项目①以中国人类遗传资源库及基因组信息为背景，采集先心病核心家系及散发病例样本，建立先心病遗传资源样本库；②通过外显子组测序技术及SNaPshot基因分型技术，在核心家系中筛选并在散发病例中确认新生突变基因及位点；③通过功能富集分析、胚胎发育过程的时空表达情况分析及蛋白互作分析等生物信息学方法确认、评估新生突变基因与先心病发生的相关性。最终确认了CDK2、IRF3等13个基因14个位点可能参与先心病的发生发展，这是在以往研究中并未报道的与先心病相关的基因及位点。本研究可为先心病发病机制的研究提供依据，对于推动精准的产前基因筛查的开展、提高先心病检出率、降低出生缺陷具有重要意义。