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.