Abstract
Objective: Amniocentesis, chorionic villi sampling and first trimester combined testing are able to screen for common trisomies 13, 18, and 21 and other atypical chromosomal anomalies (ACA). The most frequent atypical aberrations reported are rare autosomal aneuploidies (RAA) and copy number variations (CNV), which are deletions or duplications of various sizes. We evaluated the clinical outcome of non-invasive prenatal testing (NIPT) results positive for RAA and large CNVs to determine the clinical significance of these abnormal results. Methods: Genome-wide NIPT was performed on 3664 eligible patient samples at a single genetics center. For patients with positive NIPT reports, the prescribing physician was asked retrospectively to provide clinical follow-up information using a standardized questionnaire. Results: RAAs and CNVs (>7 Mb) were detected in 0.5%, and 0.2% of tested cases, respectively. Follow up on pregnancies with an NIPT-positive result for RAA revealed signs of placental insufficiency or intra-uterine death in 50% of the cases and normal outcome at the time of birth in the other 50% of cases. We showed that CNV testing by NIPT allows for the detection of unbalanced translocations and relevant maternal health conditions. Conclusion: NIPT for aneuploidies of all autosomes and large CNVs of at least 7 Mb has a low “non-reportable”-rate (<0.2%) and allows the detection of additional conditions of clinical significance.
Highlights
Chorionic villi sampling (CVS) or amniocentesis (AC) allow a definitive diagnosis of any aneuploidy or large copy number variations (CNV) by conventional karyotyping
While the scope of testing included rare autosomal aneuploidies (RAA) and large CNVs in addition to common aneuploidies, we focused on the clinical implications of atypical chromosomal anomalies (ACA)
Outcome information was only solicited systematically in high-risk result patients, one false-negative test result was reported in a dichorionic twin pregnancy where one fetus was diagnosed with trisomy 21 after receiving a negative non-invasive prenatal testing (NIPT) result
Summary
Chorionic villi sampling (CVS) or amniocentesis (AC) allow a definitive diagnosis of any aneuploidy or large CNVs by conventional karyotyping. CfDNAbased NIPT was introduced with an initial focus on common trisomies (13, 18, and 21). It has been demonstrated that structural ultrasound abnormalities and serum marker levels (below 0.2 multiples of the median (MoM)) detected during first trimester combined testing (FCT) can point to other atypical chromosomal anomalies (ACA), namely rare autosomal aneuploidies (RAA) and CNVs. it has been demonstrated that structural ultrasound abnormalities and serum marker levels (below 0.2 multiples of the median (MoM)) detected during first trimester combined testing (FCT) can point to other atypical chromosomal anomalies (ACA), namely rare autosomal aneuploidies (RAA) and CNVs These anomalies can be clinically significant and would have been missed by NIPT focused on common trisomies exclusively [4,5]. The clinical significance and prevalence of ACA as diagnosed by classic karyotyping are outlined by combined data from 16 population-based congenital anomaly registries [6]
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