Maternal copy number variations detected by noninvasive prenatal testing in Japanese women

Non-invasive prenatal testing (NIPT) is a screening method that detects fetal chromosomal trisomies from cell-free DNA in maternal blood. Because NIPT uses whole-genome sequencing with next-generation sequencing for data processing, it can also detect maternal genomic information. Although most copy number variations (CNVs) are benign, some have been reported to be associated with pathological phenotypes and are attracting increasing attention. However, most CNV studies have been conducted in Western populations, and large-scale studies in Japanese cohorts remain scarce. This study represents the first multicenter, large-scale cohort investigation of maternal CNVs in Japanese pregnant women. We analyzed 46,082 participants to establish a reliable threshold for maternal CNV detection and to evaluate their clinical significance. Maternal CNVs were validated using array comparative genomic hybridization, and receiver operating characteristic curve analysis identified 0.8 Mbp as the minimum threshold achieving 100% specificity. Applying this criterion, maternal CNVs were identified in 2907 cases (6.3%), with the most frequent being a duplication at chr8: 3,842,478-6,092,478 (hg38, allele frequency 2.67%). Comparison with public genomic databases, including the Tohoku Medical Megabank Organization (ToMMo) and the Genome Aggregation Database (gnomAD), confirmed that all CNVs detected in this study had been previously reported, with particularly high concordance in ToMMo. Notably, several very rare CNVs were also identified. These findings demonstrate that NIPT can reliably detect maternal CNVs ≥0.8 Mbp, which appear to represent benign genomic variants that are unlikely to affect fertility or early miscarriage.