探讨胎龄为16~18周系统胎儿超声检查联合胎儿全外显子组测序(WES)，对颈项透明层(NT)值≥3.5 mm，染色体正常胎儿的产前诊断价值。

选择2018年1月至2020年3月，在广州市妇女儿童医疗中心产前诊断中心就诊，于胎龄为11⁺¹~13⁺⁶周时接受胎儿超声检查提示NT值≥3.5 mm，通过绒毛活检术或羊膜腔穿刺术采集绒毛或羊水标本，进行G显带染色体核型分析(KA)及染色体微阵列分析(CMA)结果显示染色体正常的31例单胎妊娠胎儿为研究对象。于胎龄为16~18周时，对其进行系统胎儿超声检查。征得孕母知情同意后，再对上述31例胎儿进行胎儿WES分析。采用回顾性分析方法，收集其临床特点、WES结果、胎龄为16~18周系统胎儿超声检查结果和妊娠结局，并进行分析。本研究遵循的程序符合广州市妇女儿童医疗中心伦理委员会规定，并获得该伦理委员会批准(审批文号：2018110201)，所有胎儿孕母均签署临床研究知情同意书。

①本组31例NT增厚+染色体正常胎儿中，WES呈阳性者为12例，其中6例发生致病突变，6例发生可能致病突变；最常见单基因病为Noonan综合征(4例)，涉及PTPN11、RAF1基因新发突变；胎龄为16~18周系统胎儿超声检查结果显示，10例发现其他超声结构异常，2例未见其他异常；这12例胎儿均引产终止妊娠。WES呈阴性者为19例，其中4例超声发现结构畸形，15例16~18周及中、晚孕期超声检查均未见异常；对2例采取引产终止妊娠，17例继续妊娠至分娩后，1例中、晚孕期发现宫内生长受限，随访至生后6个月时，仍然存在生长发育迟缓，1例生后发现生长发育迟缓，其他15例随访至生后6个月时，生长、发育均正常。②本组31例胎龄为16~18周胎儿超声系统检查结果显示，14例(45.2%)为结构畸形，包括颅内出血(1例)、脑室扩张(3例)、Dandy-Walker综合征(1例)、先天性心脏畸形(2例)、四肢畸形(2例)、骨骼系统畸形(2例)、淋巴瘤(3例)。

胎龄为16~18周系统胎儿超声联合胎儿WES技术，可对NT增厚+染色体正常胎儿进行有效产前诊断，减少孕妇焦虑和等待时间。

To explore prenatal diagnosis value of fetal system ultrasound in gestational age of 16-18 weeks combined with fetal whole exome sequencing (WES) in fetuses with nuchal translucency (NT) value ≥3.5 mm and normal chromosomes.

From January 2018 to June 2020, a total of 31 fetuses with NT≥3.5 mm in ultrasound scan at gestational age of 11^{+ 1}-13^{+ 6} weeks and normal chromosomes in G-banding karyotype analysis (KA) and chromosome microarray analysis (CMA) by chorionic villus biopsy or amniocentesis in Guangzhou Women and Children′s Medical Center were enrolled as research subjects. All subjects underwent an extra early systematic ultrasound scan at gestational age of 16-18 weeks. WES was carried out after the extra ultrasound scan at gestational age of 16-18 weeks and was approved by pregnant mother. Clinical characteristics, WES results, fetal system ultrasound scan at gestational age of 16-18 weeks results and pregnancy outcomes of 31 fetuses were collected and analyze by retrospective method. The procedures followed in this study were approved by the Ethics Committee of Guangzhou Women and Children′s Medical Center (approval No. 2018110201). Pregnant mother of each fetus signed the clinical research informed consents.

①Among the 31 fetuses with thickened NT and normal chromosomes, 12 fetuses were positive of WES, of which 6 cases had pathogenic mutations and 6 cases had likely pathogenic mutations. Among these 12 fetuses, 4 cases had dominant de novo mutations in PTPN11 and RAF1 gene, which were associated with Noonan syndrome. Results of early systematic ultrasound scan of fetus at gestational age of 16-18 weeks showed that other ultrasound structural abnormalities were found in 10 cases, and no other abnormalities were found in 2 cases. All these 12 fetuses were induced to labor. 19 fetuses were negative of WES, of which 4 cases had structural malformations, and no abnormalities were found in the other 15 fetuses at gestational age of 16-18 weeks of systematic ultrasound and later ultrasound during pregnancy. Among these 19 fetuses, 2 cases were induced to labor, the other 17 cases continued pregnancy to delivery, of which 1 case was found to have intrauterine growth restriction in the middle and third trimesters, and growth retardation still existed after 6 months of follow-up. Among the remaining 16 cases, 1 case was found to have growth retardation after birth, and the other 15 cases were followed up to 6 months after birth and their growth and development were normal. ②Results of ultrasound system scan of 31 fetuses at gestational age of 16-18 weeks showed that 14 cases (45.2%) found structural malformations, including intracranial hemorrhage (1 case), ventricular dilatation (3 cases), Dandy-Walker syndrome (1 case), congenital heart malformations (2 cases), limb malformations (2 cases), skeletal system malformations (2 cases), and lymphoma (3 cases).

Gestational age of 16-18 weeks of fetal systematic ultrasound combined with fetal WES is an effective prenatal diagnosis method for fetus with thickened NT and normal chromosomes, which can reduce anxiety and waiting time of pregnant women.