基于三维超声容积数据模型及基因检测对Dandy-Walker综合征遗传学病因的研究

With the permission of Two Children Policy in China, the incidence rate of fetal anomalies has been increased that resulted in the high morbidity and mortality during perinatal periods. Dandy－Walker Syndrome (DWS) is the most common congenital cerebellum malformation. Genetic factor is the main pathogenic factor. Most of previous studies have recruited DWS patients after birth. It has suggested that DWS has relation to fetal chromosomal karyotype and segment abnormalities, and the studies have shown that Zic1, Zic4 and Foxc1 may be the causative genes of DWS. However,the etiology of DWS is still unclear in most cases, though it has been revealed a little by previous studies. Our research group has found that prenatal diagnosis of DWS is possible through the comparison between three-dimensional ultrasound examination of DWS and fetal autopsy, and different Copy Number Variations (CNV) have been detected which contained extra genes except known ones in our previous studies for DWS fetuses with normal chromosomal karyotype. So we speculate that foetal period is the best time for the exploration of DWS causes. Genetic abnormalities should be further detected if DWS fetuses are with normal chromosome karyotype and segments. The study is to diagnose fetal DWS with three-dimensional ultrasound volume mode and to reveal genetic causes by CNV detection and Whole Exome Sequencing of fetuses and their parents. It will provide theoretical basis for the prevention of birth defect and prenatal consultation.

随着我国二胎政策全面放开，畸形儿发生率呈上升趋势，导致围产期发病率及死亡率增高。Dandy－Walker综合征（DWS）是最常见的先天性小脑畸形，遗传是主要致病因素。既往研究多以生后患者为研究对象，发现此畸形存在染色体核型及片段异常，并定位了Zic1、Zic4和Foxc1基因，揭示了一部分病因，但仍有很多病例病因尚不清楚。本课题组前期工作中通过三维超声检测胎儿DWS并与尸检病理对照研究显示：产前诊断DWS是可行的；并在前期研究中以染色体核型正常DWS胎儿为研究对象，发现存在不同拷贝数变异（CNV），内含已知基因之外的相关基因。我们推测胎儿期研究DWS病因是最佳时期，染色体水平无异常发现的病例，可深入探索其基因异常。本课题拟采用三维超声容积数据模型产前诊断DWS，对胎儿及父母行CNV检测及全外显子组测序，寻找对应CNV及基因改变，揭示其遗传学病因，为孕期出生缺陷的干预及产前咨询提供理论依据。

随着我国二胎政策全面放开，畸形儿发生率呈上升趋势，导致围产期发病率及死亡率增高。颅后窝异常是一组以颅后窝结构异常为主要表现的颅脑先天性疾病，包括的亚型较多，有Dandy-Walker综合征、小脑蚓部发育不良等。这些亚型预后差异较大，表现轻重不一，临床表现可从无明显异常至重度神经发育障碍。因此，产前及时诊断胎儿颅后窝异常，准确判断其亚型，揭示其遗传学病因，对胎儿产前咨询与预后评估非常重要。本研究应用三维超声容积成像技术产前评估Dandy-Walker综合征等颅后窝异常病例，发现三维超声容积定量指标在产前诊断颅后窝异常及预后评估中均起到重要作用。三维超声容积数据定量指标中，小脑蚓部面积、脑干-蚓部夹角与脑干-小脑幕夹角对疾病预后预测的ROC曲线下面积分别为0.901、0.689和0.761，其中小脑蚓部面积与疾病预后关系密切，并初步建立了超声诊断数据模型。三维超声相比二维超声诊断正确率由60.0%提高至94.8%。同时，本研究以胎儿标本为研究对象，分别从胎儿染色体核型、拷贝数变异和/或基因水平研究颅后窝异常胎儿的遗传学病因。我们发现颅后窝异常胎儿产前进行遗传学检测可揭示一部分病因，有利于早期诊断及判断胎儿预后，指导再次妊娠，为孕期出生缺陷的干预及产前咨询提供有帮助的信息。

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