Contribution of maternal copy number variations to false‐positive fetal trisomies detected by noninvasive prenatal testing

OBJECTIVE: The aim of the study was to determine the contribution and significance of maternal copy number variations (CNVs) to false-positive noninvasive prenatal testing (NIPT) trisomy results. METHODS: A total of 112 021 patients were referred for NIPT. Fetal aneuploidy testing was performed using low coverage massively parallel sequencing, and results reported as chromosome Z-scores. Copy number variation sequencing (CNV-Seq) was used to detect maternal DNA CNVs. RESULTS: Confirmatory amniocentesis and karyotyping of 563 of 781 patients (72%) receiving a positive trisomy result revealed 489 true and 74 false positives. In 6 of these 74 patients (8.1%), CNV-Seq revealed non-pathogenic maternal duplications (1.76-10.90 megabases) on the chromosome associated with the fetal trisomy. There was a strong correlation of higher Z-scores with increasing size of the maternal CNVs (R2  = 0.94). When the contribution of the maternal CNV-Seq reads to chromosome Z-scores were removed, all original Z-scores shifted to the normal range. CONCLUSIONS: Maternal CNVs can potentially contribute to a small but significant number of false-positive fetal trisomies detected by NIPT. To avoid unnecessary invasive procedures and better manage patients, we recommend that confirmatory maternal DNA sequencing is performed when the NIPT methodology used indicates a high risk of a maternal CNV. © 2017 John Wiley & Sons, Ltd.