Objective：To investigate the value of whole exome sequencing（WES）in cases of fetal abnormalities diagnosed by prenatal ultrasound（including structural malformations and soft markers）where chromosome microarray analysis（CMA）failed to clarify the cause. Methods：A total of 81 fetuses were selected from the Department of Ultrasound at the Affiliated Obstetrics and Gynaecology Hospital of Nanjing Medical University，who were diagnosed with fetal abnormalities between January 2022 and January 2024. Following genetic counseling，invasive prenatal diagnoses were chosen，and chorionic villus sampling or amniocentesis was performed for CMA testing，which yielded negative results. WES analysis was then conducted on these samples. The determination of genetic variants was classified according to the guidelines of the American Society for Medical Genetics and Genomics（ACMG）. Pathogenic and possibly pathogenic variants were categorized as positive results，while clinical significance unknown，benign，and possibly benign were categorized as negative results. Results：The 81 ultrasound anomalies consisted of 47（58.02%）monosystemic and 34（41.98% ）multisystemic anomalies. WES detected a total of 14（17.28% ）positive cases，including 7 cases each of monosystemic and multisystemic anomalies，while the remaining 67 cases（82.72%）were negative. The most common ultrasound abnormalities in positive fetuses were cardiovascular system abnormalities and skeletal system abnormalities，each occurring in 5 cases （35.71%），followed by urinary system abnormalities in 4 cases（28.57%）. In addition，2 fetuses had combined nuchal translucency （NT）thickening at early stage（14.29%），and multiple abnormalities were found by ultrasound at mid-trimester. Conclusion：Fetuses with ultrasound anomalies，especially when combined with cardiovascular，skeletal，urinary anomalies or multisystem anomalies，are recommended to undergo WES testing if CMA testing fails to clarify the etiology，which may identify new potential causative genes.