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.
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing, China.
Xiya
X
Zhou
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing, China.
Lili
L
Sui
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing, China.
Yalan
Y
Xu
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing, China.
Yijun
Y
Song
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing, China.
Qingwei
Q
Qi
Berry Genomics Corporation, Beijing, China.
Jianguang
J
Zhang
Berry Genomics Corporation, Beijing, China.
Hongmin
H
Zhu
Berry Genomics Corporation, Beijing, China.
Huaiyu
H
Sun
Berry Genomics Corporation, Beijing, China.
Feng
F
Tian
Berry Genomics Corporation, Beijing, China.
Mengnan
M
Xu
Berry Genomics Corporation, Beijing, China.
David S
http://orcid.org/0000-0002-2587-2476
DS
Cram
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing, China.
Juntao
J
Liu
D000328:Adult; D056915:DNA Copy Number Variations / Q000235:genetics*; D003951:Diagnostic Errors; D005189:False Positive Reactions; D005260:Female; D005315:Fetal Diseases / Q000175:diagnosis* / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007621:Karyotyping / Q000379:methods; D009035:Mothers; D011247:Pregnancy; D011296:Prenatal Diagnosis / Q000379:methods*; D017422:Sequence Analysis, DNA / Q000379:methods; D014314:Trisomy / Q000175:diagnosis* / Q000235:genetics