Abstract
BACKGROUND: The aim of this study was to investigate the detection capability of medium-coverage whole-genome sequencing for chromosomal mosaicism in prenatal diagnosis, and to evaluate the pregnancy outcome of mosaicism. METHODS: Thirty-four prenatal samples with chromosomal mosaicism diagnosed by chromosomal microarray analysis with single nucleotide polymorphism (CMA/SNP) were included and subsequently subjected to chromosome analysis by medium-coverage whole-genome sequencing (CMA-seq) for back-to-back comparison. The results of karyotyping or fluorescence in situ hybridization (FISH) were reviewed for additional validation. Data on pregnancy outcomes were collected to analyze the effect of mosaicism on fetuses. RESULTS: In total, 13 mosaic autosomal trisomies, 9 sex chromosome aneuploidies (SCAs), and 12 mosaic copy number variants (CNVs) (11 pathogenic or likely pathogenic) were detected by CMA-seq. Twenty-six cases were classified as having high-level (≥ 30%) mosaicism, and 8 were classified as having low-level (< 30%) mosaicism. The results of mosaicism detected by CMA-seq were in 100% agreement with those of CMA/SNP. Among the 25 cases with consistent FISH or karyotyping results, 4 had three cell lines, and 8 had mosaicism involving complex structural aberrations. Except for 2 mosaic SCAs and 1 mosaic CNV of uncertain significance, all pregnancies in the high-level group were terminated, whereas most fetuses without ultrasound abnormalities in the low-level group were delivered. CONCLUSIONS: The efficiency of CMA-seq in detecting mosaicism is comparable to that of CMA/SNP. Combining cytogenetic and molecular genetic methods can provide a comprehensive interpretation of mosaicism. The mosaic level, pathogenicity of chromosomal aberrations, and ultrasound findings are the main factors for prenatal decision-making. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12884-025-08018-9.