Fetal Copy Number Variant Detection in Pregnancies with Ultrasound Soft Markers: A Maternal Age-Stratified Retrospective Study.

BACKGROUND: Prenatal ultrasound soft markers are common indicators for fetal genetic screening, while the correlation between maternal age and fetal copy number variant (CNV) detection remains controversial. This study aimed to analyze CNV characteristics in fetuses with ultrasound soft marker abnormalities and explore the influence of maternal age on CNV detection. METHODS: A total of 468 fetuses with abnormal ultrasound soft markers were enrolled and divided into <35 years (n=390) and ≥35 years (n=78) groups based on maternal age. Chromosomal microarray analysis (CMA) was performed for the enrolled fetuses. Fetal pathogenic/likely pathogenic (P/LP) CNVs and variants of uncertain significance (VUS) were detected and statistically analyzed. RESULTS: The overall detection rates of P/LP CNVs and VUS were 4.1% and 9.0%, respectively. Notably, the P/LP CNVs detection rate was significantly higher in women aged <35 years (4.9%) than in those aged ≥35 years (0%, p=0.047). The CNVs detection rate was 14.0% in fetuses with a single soft marker abnormality and 7.5% in those with ≥2 abnormal soft markers; the difference did not reach statistical significance (p=0.138). No significant inter-group difference was found in VUS detection rate and CNV detection rates of different types or numbers of soft markers (all p>0.05). In cases with single ultrasound soft marker abnormality, The CNV detection rate was the highest in cases with pyelic separation (n=19), reaching 26.3%; echogenic bowel (n=14) ranked second with a detection rate of 21.4%. CONCLUSION: As a single‑center retrospective study with underpowered subgroup analyses, our findings suggest that younger pregnant women with ultrasonic soft‑marker abnormalities may still carry risk of fetal pathogenic CNVs. CMA should be considered in pregnancies with ultrasonic soft marker abnormalities after individualized counseling, regardless of maternal age.