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Abstract To explore the value of prenatal systematic ultrasonography combined with whole exome sequencing (WES) technology for diagnosing fetuses with normal karyotype by chromosome microarray analysis (CMA) and with abnormal skeletal development in four limbs by ultrasonography. Methods: From March 2021 to January 2022, a total of 76 pregnant women with fetal nuchal translucency (NT)≥3.5 mm by ultrasound scan during 11+1-13+6 gestational weeks, but the chromosomes by G banding karyotype analysis (KA) and the CMA of these fetuses were normal. The fetuses of these women were further given WES technology, and the systematic fetal ultrasonography was performed on these fetuses during 16-18 gestational weeks. The data of the CMA and the pregnancy outcomes of these fetuses were collected. The value of prenatal systematic ultrasonography combined with WES technology for diagnosing abnormal skeletal development in four limbs of the fetuses was analyzed. The results of systematic fetal ultrasonography showed that there were 14 (18.4%) cases with skeletal structure malformations, including 5 cases of polydactyly, 3 cases of syndactyly, 3 cases of radius short, 2 cases of missing toe, and 1 case of varus, and which were all confirmed of abnormalities of skeletal system and limb after terminated pregnancy of induced labor. There were 15 (19.7%) cases with positive WES (pathogenic or potentially pathogenic gene mutation), and the osteogenic dysplasia and achondroplasia were the most common. These 15 fetuses with gene mutation were verified by Sanger sequencing. There were 8 fetuses with autosomal dominant, and the sources of the mutations were all new mutations, mainly involving COL1A1, COL1A2, and FGFR3 genes. There were 4 fetuses with autosomal recessive inheritance, and the sources of the mutations were from father or mother. There were 3 fetuses with mutation unknown cases, and the source of the mutation was unknown. In the 15 fetuses with positive WES (detected the pathogenic or possibly pathogenic gene mutation), there were 12 fetuses with skeletal abnormalities in the limbs and 3 fetuses without abnormalities by systematic fetal ultrasound during 16-18 gestational weeks. Among them, 13 fetuses were given terminate pregnancy by induced, and 2 fetuses were continued pregnancy, which included 1 newborn with strephenopodia confirmed after birth and 1 newborn with nanism of the results of follow-up to 6 months after born. Among the 61 fetuses with negative WES, 2 cases had been showed bone malformations by systematic ultrasound, and the other 59 cases had showed no abnormalities by ultrasound examination during 16-18 gestational weeks and during the second and the third trimester of pregnancy. In the 59 cases without abnormalities by ultrasound examination, 1 case terminated pregnancy, and the other 58 cases were continued pregnancy until delivery and were followed up to 6 months after delivery, with normal growth and normal development of limbs bone. Conclusion: Prenatal systematic ultrasonography combined with WES technology can provide effective prenatal diagnosis for the fetuses with normal karyotype and abnormal skeletal development in four limbs, so as to shorten the waiting time of the pregnant women.
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