High false‐positive non‐invasive prenatal screening results for sex chromosome abnormalities: Are maternal factors the culprit?

Abstract Objective To explore the impact of maternal sex chromosome aneuploidies (SCAs) and copy number variation (CNV) on false‐positive results of non‐invasive prenatal screening (NIPS) for predicting foetal SCAs. Methods In total, 22 844 pregnant women were recruited to undergo NIPS. Pregnant women with high‐risk of SCAs underwent prenatal diagnosis and maternal copy number variation sequencing (CNV‐seq). Results Among 117 women with high‐risk of SCAs, 72 accepted prenatal diagnosis, 86 accepted maternal CNV‐seq, and 21 had maternal sex chromosome abnormalities. The abnormality rate was significantly higher than women at low‐risk of SCAs (24.42% vs 3.51%). Using a novel parameter cffDNA (ChrX)/cffDNA, when the ratio was greater than 2, all foetuses had normal karyotype, and 75.0% (6/8) had abnormal maternal chromosome X. If the ratio was less than or equal to 2, only 10% (4/40) of the mothers had chromosome X CNV alterations, while 33.3% (13/40) of their foetuses had sex chromosomes CNV abnormalities. Conclusions Approximately 25% of pregnant women with SCAs predicted by NIPS had sex chromosome abnormalities as determined by CNV‐seq. The ratio of cffDNA (ChrX)/cffDNA can tentatively distinguish the maternal or foetal origin of abnormal cell‐free DNA. In a reanalysis of previous NIPS data, false‐positive results caused by maternal CNV might be elucidated.