表型不一致的先天性心脏病同卵双生子的染色体相关区域和关键基因的定位及研究

先天性心脏病是最常见的先天性畸形之一，严重危害着儿童的健康，研究先天性心脏病发生的相关基因及分子机制将为先天性心脏病的早期诊断、遗传咨询和治疗提供基础。同卵双生子有着几乎完全一致的遗传背景和宫内环境，绝大多数具有几乎完全相同的表型，少数表型不同的同卵双生子是人类性状和疾病遗传学研究的极好材料。对心脏表型不一致的同卵双生子进行研究，可能明确先天性心脏病发生相关的致病因素。本课题收集其一患先天性心脏病，另一为正常的罕见同卵双生子数对，首先分析他们是否存在宫内双胎输血综合征；对无明显宫内异常的样本进行SNP分析证实确为同卵双生子对，进一步通过染色体核型分析和比较基因组杂交芯片分析有无染色体结构的异常，对异常染色体区段进行分析；对无染色体结构异常的同卵双生子对进行全外显子测序分析，寻找突变位点；根据上述结果寻找重要的候选基因分析差异基因的表达与功能，探索先天性心脏病发生的分子机制。

Congenital heart disease, one of the most common congenital malformations, seriously endangers the health of children. The analysis of genetic and molecular mechanisms may provide evidences for early diagnosis, genetic counseling and treatment for the congenital heart disease. Monozygotic(MZ) twins inherit nearly identical genetic material and have the nearly same intrauterine environment. The vast majority of monozygotic twins have nearly identical phenotypes, but there are rare MZ twins with discordant phenotypes.These discordant MZ twins have been a valuable source of information about the genetic basis of complex traits. In the study, we collect rare MZ pairs of twins, only one of whom has congenital heart disease and the other is normal. Then, we will ①Analyze if there is "twin to twin transfusion syndrome" in these MZ pairs of twins; ②Analyze SNP to confirm they are monozygotic twins; ③Analyze karyotype and array-based comparative genomic hybridization. At the level of chromosome,the number, morphology or structure of chromosomes may vary. We will analyze the abnormal chromosome section; ④Do exome sequencing & analysis. At the level of molecular genetics, post-zygotic DNA mutation may account for different phenotype between MZ pairs of twins. We further analyze the expressions and functions of the important different genes beteween MZ pairs of twins and explore the molecular mechanisms of congenital heart disease.