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.