Interpretation
The yields of aneuploidy and pCNV varied among the anatomical systems affected. Our results support that CNV analysis should be performed in fetuses with structural anomalies,19 especially for fetuses with cystic hygroma, fetal hydrops, and abdominal wall defect, as the yield of aneuploidy/pCNV in these three anomalies was 21.14%-38.64%. Among 12 isolated ultrasonographic anomalies, this study discovered several well-known pCNV-associated organ systems (cardiovascular, genitourinary, skeletal and central nervous systems),15, 25 and provided sufficient evidence for rarely reported associations between abdominal wall defect, facial and respiratory systems, and fetal growth restriction and pCNV (Table S4). Notably, we firstly revealed that isolated abdominal wall defect was strongly associated with pCNV, in addition to its known association with aneuploidy.37 The yield of pCNV in fetuses with abnormal amniotic fluid and fetal hydrops showed no significant difference from that in fetuses with no identifiable anomalies, indicating that pCNV may be not the main genetic cause of these two anomalies. Notably, the yield of aneuploidy for fetal hydrops was up to 34.85%, especially when fetal hydrops combined with cystic hygroma, the rate was as high as 64.94%. Therefore, quantitative fluorescence polymerase chain reaction (QF-PCR) may be recommended for these fetuses before CNV analysis.
Previous studies have reported the benefits of CNV analysis in the etiological diagnosis of fetuses with isolated increased nuchal translucency and mild ventriculomegaly, with pCNV yields of approximately 2.5-5.0% and 2.0-4.4% 20, 21, 23, 38, 39 , respectively (Table S5). The yields in our study was 4.10% and 4.40%, respectively, both significantly higher than those in fetuses with no identifiable anomalies, which support CNV analysis for these two soft markers. Although the SMFM recommended that karyotyping or CNV analysis for thickened nuchal fold should be based on clinical conditions and patients preferences40, our results showed that it was worth performing CNV analysis, as fetuses with thickened nuchal fold had the highest yield of pCNV and showed significantly higher yield in pCNV. However, we could not replicate the previous associations between aberrant right subclavian and short femur/humerus length and pCNV.23 Our study represents the one of the largest CNV analysis thus far. Based on our results, we suggest careful prenatal decision-making for fetuses with these two soft markers. Interestingly, we found that single umbilical artery was significantly associated with pCNV, contrary to a previous study of 126 fetuses.23 This difference may be explained by the sample size, which requires replicated cohorts for further verification.
We replicated previous well-known pCNV-phenotype associations such as 22q11.2 deletion41 and 7q11.23 deletion42 with cardiovascular defect, 17q12 deletion with genitourinary system defect 43, and 4p16 deletion with fetal growth restriction 44. Simultaneously, skeletal system abnormalities were strongly associated with 16p11.2 deletion, which was rarely reported in previous studies. Except for the known association with fetal growth restriction, 4p16.3-p16.1 deletion showed a novel association with genitourinary system. Additionally, this study firstly observed that 3p26.3-p26.1 and 13q33.3-q34 deletions and 3q25.2-q29 duplication were associated with abdominal wall defect, respiratory system, and cystic hygroma and abdominal wall defect, respectively, expanding the phenotypic spectrum of such unusual pCNV. Moreover, our findings show that fetuses with 22q11.21 deletion had a lower percentage of choroid plexus cysts than fetuses without chromosomal aberrations, suggesting that choroid plexus cysts were less likely to occur in fetuses with 22q11.21 deletion.