Prenatal Diagnosis of Foetal Structural Anomalies Using Medium-Coverage Whole Genome Sequencing (CMA-Seq): A Large-Scale Comparative Study With CMA in 3973 Pregnancies.

OBJECTIVE

To evaluate the feasibility and effectiveness of medium-coverage whole genome sequencing (CMA-seq) for prenatal diagnosis of foetal structural anomalies, and to compare its performance with conventional chromosomal microarray analysis (CMA).

DESIGN

A prospective clinical study combined with a systematic meta-analysis.

SETTING

A tertiary maternal and child health hospital in Chongqing, China.

POPULATION OR SAMPLE: 3973 pregnant women with ultrasound-detected foetal structural anomalies or other high-risk indications.

METHODS

Specimens were collected through amniocentesis, followed by CMA-seq to identify a wide range of chromosomal abnormalities. Meta-analysis was used to study the application and effectiveness of CMA in prenatal diagnosis. Clinical studies were screened in Chinese and English databases, and a meta-analysis was performed.

MAIN OUTCOME MEASURES: Detection rates for chromosomal abnormalities, including mosaic aneuploidy, small copy number variants (CNVs < 100 kb) and absence of heterozygosity.

RESULTS

CMA-seq identified chromosomal abnormalities in 24.72% (982/3973) of cases. Mosaic aneuploidy was detected in 6.5% of samples (42 cases < 30% mosaicism). A total of 670 cases were presented with CNVs, including 40 below 100 kb. AOH was found in 112 cases (2.82%). The meta-analysis indicated a lower pooled chimeric chromosome detection rate (1.10%), a smaller proportion of CNVs < 500 kb (2.06%), and reduced AOH detection (1.26%) with conventional CMA.

CONCLUSION

CMA-seq exhibits significant advancements and superior sensitivity in detecting low-level mosaic aneuploidy, small segment CNVs and AOH.