Low-pass genome sequencing reveals associations between copy number variations and fetal ultrasonographic anomalies and soft markers in a cohort of 43,721 fetuses

Objective: To systematically explore the association between pathogenic/likely pathogenic copy number variations (pCNV) and ultrasonographic anomalies and soft markers. Design Retrospective cohort study. Setting Data were obtained from multiple centers in china. Population or Sample Fetuses performed low-pass genome sequencing and ultrasonography between 2016 and 2020. Method The yields of pCNV under various ultrasonographic indications were compared with that of fetuses with no identifiable anomalies. In addition, the ultrasonographic characteristics of aneuploidy and pCNV were described in comparison with those of fetuses without chromosomal aberrations. Main Outcome Measures Yields of aneuploidy and pCNV in different ultrasonographic indications. Results Ten of the 12 ultrasonographic anomalies had significantly higher yield of pCNV, except for fetal hydrops and abnormal amniotic fluid, of which the gastrointestinal, facial, respiratory systems, and abdominal wall defect were rarely reported. Similarly, five of the 12 soft markers had significantly higher yield of pCNV, with single umbilical artery being rarely reported. Furthermore, this study reported that four duplications/deletions were associated with novel ultrasonographic findings. Conclusions Based on specific ultrasonographic phenotypes, prenatal genetic testing could be considered in a tailored fashion. Keywords Low-pass genome sequencing; ultrasonographic anomaly; soft marker; copy number variations; aneuploidy; prenatal diagnosis Tweetable abstract Fetuses with structural anomalies and specific soft markers are recommended for copy number variations analysis