摘要目的:评估全外显子测序技术（WES）在产前临床应用于传统产前诊断阴性的异常胎儿的价值。方法:对2014年1月至2019年12月在广州市妇女儿童医疗中心行侵入性产前诊断［包括G显带染色体核型分析和（或）染色体微阵列分析（CMA）检测］，结果为阴性的1 152例先天性发育异常（包括先天性结构畸形及超声软指标异常）胎儿进行核心家系WES检测。根据WES检测的时间节点与妊娠终止的关系，分为回顾组（妊娠已终止）及前瞻组（妊娠未终止）。根据胎儿畸形的具体发生部位区分各器官畸形亚组，并根据家族史情况分亚组。随访所有入选胎儿的临床预后，并统计WES检测结果对妊娠决策及临床干预的影响。根据随访结果，对初次WES检测未获得阳性诊断但孕晚期或出生后有新增表型胎儿的数据进行重分析。结果:接受WES检测的1 152个家系中有5例检出非胎儿生物学父母而被剔除，其余1 147例中共152例胎儿获得阳性诊断（13.3%，152/1 147），包括回顾组74例（16.1%，74/460），前瞻组78例（11.4%，78/687）。对未获得阳性诊断但孕晚期或出生后出现新增表型的胎儿进行WES检测数据的重分析，阳性诊断率为4.9%（8/163）。共34例（21.3%，34/160）受检者的妊娠结局及临床干预直接受对应的WES阳性诊断影响。在诊断性变异为4级的68例活产儿中，29例（42.7%，29/68）通过快速回顾WES结果获得了适当的医学干预。结论:WES对染色体核型分析和（或）CMA阴性的异常胎儿可额外提高13.3%的检出率。产前WES可指导妊娠决策及早期临床干预。重视妊娠晚期及胎儿出生后的专科随访并进行WES数据重分析是提高检出率的有效策略。

abstractsObjective:To evaluate the value of whole exome sequencing (WES) in prenatal clinical application.Methods:A total of 1 152 cases of congenital abnormal [including structural malformation, nuchal translucency (NT) thickening and intrauterine growth restriction] with traditional prenatal diagnosis [including G-band karyotype analysis and chromosome microarray analysis (CMA)] negative were analyzed. The congenital abnormal fetuses were divided into retrospective group and prospective group according to the time of WES detection, that is whether the pregnancy termination or not. According to the specific location of fetal malformation and their family history, the cohort was divided into subgroups. The clinical prognosis of all fetuses were followed up, and the effect of WES test results on pregnancy decision-making and clinical intervention were analyzed. According to the follow-up results, the data of fetuses with new phenotypes in the third trimester or after birth were re-analyzed.Results:Among 1 152 families who received WES, 5 families were excluded because of nonbiological parents. Among the remaining 1 147 families, 152 fetuses obtained positive diagnosis (13.3%,152/1 147), including 74 fetuses in the retrospective group (16.1%,74/460) and 78 fetuses in the prospective group (11.4%,78/687). In fetuses with negative CMA and G-band karyotype analysis results but new phenotypes in the third trimester or after birth, the positive rate by WES data re-analysis was 4.9% (8/163). A total of 34 (21.3%, 34/160) fetuses were directly affected by the corresponding positive molecular diagnosis. Among 68 cases of live births with diagnostic variation grade 4, 29 cases (42.7%, 29/68) received appropriate medical intervention through rapid review of WES results.Conclusions:WES could increase the detection rate of abnormal fetuses with negative G-banding karyotype analysis and CMA by 13.3%. Prenatal WES could guide pregnancy decision-making and early clinical intervention. It might be an effective strategy to pay attention to the special follow-up of the third trimester and postnatal fetus and to re-analyze the WES data.