三维超声标准化分类联合CMA检测对胎儿后颅窝异常表型与基因型关系的遗传学研究

There is a wide variety of posterior cranial fossa abnormalities (PFAs) in fetus, and their genetic mechanisms are not clear now. Even the fetuses with PFAs show very similar ultrasonographic appearance, the prognosis could be radically different. This distinct characteristic brings serious difficulties in prenatal genetic counseling. In our preliminary research, some genomic copy-number variants (CNVs) and related genetic syndromes were detected in certain cases of PFAs using chromosome microarray analysis (CMA). These cases with PFAs were firstly detected by prenatal ultrasound, and their karyotypes were shown normal. It is suggested that CNVs might be one of the significant genetic mechanisms for PFAs. So, whether the relationship between CNVs and different types of PFAs are the same? What kind of connection exists between the CNVs genotype and ultrasound phenotype in fetus with PFAs? To solve the scientific problem above, the prerequisite is to make an accurate diagnose and precise classification for fetus with PFAs. Therefore, this study attempt to apply three-dimensional ultrasound to quantify PFAs ultrasound phenotype in fetus which is based on our previous study, and develop a standardized prenatal classification system. Then the CMA methods were employed to identify genetic material variants in fetus with PFAs, in order to further explore the relationship between the PFAs genotype and phenotype, and finally establish a fetal ‘ultrasonic phenotype – genotype’ database of PFAs innovatively. PFAs ultrasound manifestation related genetic material database. This study will promote the clinical application of the ‘structure-genomics’ diagnostic pattern and conducive to further genetics pathogeny study of PFAs, that is significant in guiding aristogenesis.

胎儿后颅窝异常种类繁多且遗传机制不明，超声表现相近的患儿预后可截然不同，为优生咨询带来极大困难。课题组前期应用染色体微阵列芯片分析（CMA）技术，在超声提示后颅窝异常而核型正常的胎儿中检出拷贝数变异（CNVs），发现了一些遗传综合征，提示CNVs可能是后颅窝异常的重要遗传机制。那么，各类后颅窝异常与CNVs的相关性是否相同？这些CNVs基因型与胎儿后颅窝异常的超声表型有着何种关联？以上科学问题的研究，其先决条件是胎儿后颅窝异常的准确诊断及精确分类。由此，本课题拟在前期研究基础上，以三维超声量化胎儿后颅窝异常超声表型为突破口，建立标准化产前分类诊断体系，并联合CMA检测胎儿后颅窝异常可能存在的遗传物质改变，以寻找表型与基因型的规律，创新性的建立胎儿后颅窝异常“超声表型-基因型”数据库。本项目的进行对促进结构-基因相结合的诊断方式、后颅窝异常遗传学机制的深入研究、指导优生优育具有重要意义。

胎儿后颅窝疾病分类繁杂，其遗传学机制尚不明确，为优生咨询带来极大困难。课题组应用染色体微阵列芯片分析（CMA）技术，发现了一些后颅窝异常相关遗传综合征，为进一步探索各类后颅窝异常与CNVs的相关性，以及基因型与超声表型的关联，本课题对胎儿后颅窝异常应用三维超声存储图像信息，以三维超声量化胎儿后颅窝异常超声表型为突破口，建立了标准化产前分类诊断体系，并联合CMA检测胎儿后颅窝异常可能存在的遗传物质改变，以寻找表型与基因型的规律，建立了不同种类后颅窝产前超声表型和遗传物质改变的数据库，完善了基因组层面的后颅窝异常遗传机制信息。研究组按照项目计划开展研究，依据所设计的技术路线实施研究，实现了主要研究目标并取得了以下成果：.（1）应用三维超声技术建立了胎儿后颅窝异常产前超声诊断和分型的数据模型，完善了后颅窝异常产前超声表型标准化分类体系，在此基础上研发了计算机辅助超声诊断胎儿颅脑异常模型。.（2）对比了染色体核型分析及CMA技术对后颅窝异常胎儿染色体异常的检出情况，建立了各类型后颅窝异常的产前超声表型与遗传物质改变比对数据库。.（3）基于上述超声表型与遗传物质改变比对数据库，筛选了各类型后颅窝异常相关致病CNVs，从基因组层面进一步揭示了后颅窝异常的发病机制，建立了超声表型与基因型的相关性，进一步完善了产前遗传学咨询体系。.（4）课题期间共接收SCI论文6篇，国内核心期刊论文1篇；项目负责人同时受中国医师协会资助前往英国伦敦圣乔治医院胎儿医学中心访学半年，受邀参加广东省医师协会超声医师分会年会并专题发言，参加各级学术会议数次，课题组两名核心成员晋升副教授，2名晋升中级职称，3名博士研究生均已顺利完成研究并获得学位。

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