Genetic Testing and Pregnancy Outcome Analysis of 362 Fetuses with Congenital Heart Disease Identified by Prenatal Ultrasound

Abstract Background: Congenital heart defects (CHD), as the most common congenital anomaly, have been reported to be associated with chromosomal abnormalities. Currently, patients with CHD are routinely offered karyotyping and chromosomal microarray (CMA) testing, but the genotype-phenotype relationship has not yet been fully established. Objective: To determine the type and frequency of chromosomal abnormalities in fetuses with CHD and to analyze pregnancy outcomes of fetuses with heart abnormalities caused by different genetic factors. Methods: A total of 362 cases of CHD were enrolled from 2009 to 2016. Detailed ultrasound and laboratory examinations, including karyotyping and CMA, were performed. Outcome was obtained from discharge summaries. Results: Of the 362 fetuses, 220 were found with an isolated CHD, and 142 had CHD with extracardiac anomaly. Among these 362 fetuses, 140 were identified with a genetic cause, including 111 cases with aneuploidy, 10 cases with abnormality of chromosomal structure by karyotyping and 19 cases with pathogenic or likely pathogenic copy-number variations (CNVs) by CMA. The detection rate is close to 38.7%. Only one (identified as trisomy 18 syndrome) in 140 positive cases resulted in perinatal death, with the others being induced. The remaining 222 cases had negative results for both genetic testing and of these cases, 56 resulted in induced labor, and 77 had natural childbirth or caesarean births. The pregnancy outcome of the remaining 89 cases was uncertain. Conclusions: Karyotyping and CMA are effective and accurate prenatal genetic techniques for identifying fetal chromosomal abnormalities associated with cardiac defects, and this can assist clinical doctors to perform appropriate genetic counselling with regard to the etiology and outcome of CHD.

【背景】先天性心脏病（Congenital heart defects, CHD）作为最常见的先天性畸形，已被证实与染色体异常存在关联。目前临床常规对先天性心脏病患者实施核型分析与染色体微阵列分析（Chromosomal microarray, CMA）检测，但基因型-表型关联尚未完全明确。【研究目的】明确合并先天性心脏病的胎儿的染色体异常类型与发生频率，并分析不同遗传因素所致心脏异常胎儿的妊娠结局。【研究方法】本研究于2009年至2016年间纳入362例先天性心脏病胎儿病例，对所有受试者开展详细超声检查及包括核型分析、染色体微阵列分析在内的实验室检测，妊娠结局通过出院小结进行获取。【研究结果】362例胎儿中，220例为单纯性先天性心脏病，142例合并心外畸形。其中140例检出明确遗传病因：111例为非整倍体异常，10例经核型分析检出染色体结构异常，19例经染色体微阵列分析检出致病性或疑似致病性拷贝数变异（Copy-number variations, CNVs），总检出率约为38.7%。140例阳性病例中仅1例（确诊为18-三体综合征）发生围产期死亡，其余均行引产术。剩余222例遗传学检测结果均为阴性，其中56例引产，77例经阴道分娩或剖宫产分娩；其余89例的妊娠结局尚不明确。【研究结论】核型分析与染色体微阵列分析是检出合并心脏畸形胎儿染色体异常的高效、精准产前遗传学检测技术，可辅助临床医师针对先天性心脏病的病因与妊娠结局开展适宜的遗传咨询。