Xiang J, Li R, He J, et al. Am J Obstet Gynecol MFM. 2023;5(1):100790. doi:10.1016/j.ajogmf.2022.100790.

Tags: Clinical Experience / Clinical Utility, 2023, China, RAAs

• “Results: Overall, 154 rare autosomal trisomies were identified in 89,242 pregnancies (0.17%) through noninvasive prenatal testing. In the 120 cases in which cytogenetic and molecular investigations were carried out, the rare autosomal trisomies were found to originate from true fetal mosaicism (n=5), uniparental disomy (n=5), maternal mosaic trisomy (n=3), maternal malignancy (n=1), and confined placental mosaicism (n=106). Clinical follow-up showed that 40% of all rare autosomal trisomy cases had adverse perinatal outcomes. In women with false-positive noninvasive prenatal testing results originating from confined placental mosaicism, the frequency of adverse perinatal outcomes was 26%. More importantly, the placental mosaicism ratio revealed by noninvasive prenatal testing was significantly higher in women who experienced adverse perinatal outcomes than those who did not (0.688 vs 0.332; P<.001).”
• “Conclusion: Women with noninvasive prenatal testing results indicative of rare autosomal trisomies are at risk of adverse perinatal outcomes, and that risk can be stratified using chromosomes and the mosaicism ratio revealed by noninvasive prenatal testing. Our data are valuable for obstetrical caregivers advising a patient with a noninvasive prenatal testing result indicative of a rare autosomal trisomy and a false-positive diagnosis and for managing risks during pregnancy.”

van der Meij KRM, van de Pol QYF, Bekker MN, et al. Eur J Hum Genet. 2023;31(5):555-561. doi:10.1038/s41431-022-01248-x. Open Access: Learn more

Tags: Patient Perspectives, 2023, Netherlands, RAAs, CNVs

• A pre-and post-test questionnaire was completed by 473 women choosing between targeted NIPT and GW-NIPT through the Dutch TRIDENT-2 study.
• “Most respondents (90.4%) were glad to have been offered the choice between GW-NIPT and targeted NIPT; 76.5% chose GW-NIPT. Main reasons to choose GW-NIPT were ‘wanting as much information as possible regarding the child’s health’ (38.6%) and ‘to be prepared for everything’ (23.8%). Main reasons to choose targeted NIPT were ‘avoiding uncertain results/outcomes’ (33.7%) and ‘not wanting to unnecessarily worry’ (32.6%). Nearly all respondents received a low-risk NIPT result (98.7%). No differences were found in anxiety between women choosing GW-NIPT and targeted NIPT. Most respondents were favorable toward future prenatal screening for a range of conditions, including life-threatening disorders, mental disabilities, disorders treatable in pregnancy and severe physical disabilities, regardless of their choice for GW-NIPT or targeted NIPT. In conclusion, women who chose first-tier NIPT were satisfied with the choice between GW-NIPT and targeted NIPT, and most women were favorable toward a broader future screening offer.”

Liu S, Chang Q, Yang F, et al. Arch Gynecol Obstet. 2023;308(3):787-795. doi:10.1007/s00404-022-06908-3.

Tags: Clinical Experience / Clinical Utility, 2023, China, RAAs

• “NIPT results were available for 41,819 cases; 691 positive cases were reported. The overall sensitivity for detection of T21, T18, T13, SCA, and RCA [rare chromosome aneuploidies] was 99.21, 100.00, 100.00, 98.55, and 100.00%, and the specificity was 99.95, 99.94, 99.98, 99.69, and 99.92%, respectively. The positive predictive values (PPVs) for detection of T21, T18, T13, SCA, and RCA were 85.62, 45.24, 40.00, 34.17, and 13.51%, respectively.”

Zou Y, Feng C, Qin J, et al. Front Genet. 2023;13:1073851. Published 2023 Jan 13. doi:10.3389/fgene.2022.1073851. Open Access: Learn more

Tags: Clinical Experience / Clinical Utility, 2023, China, RAAs, CNVs

• Of 23,116 patients, 264 (1.14%) had a positive NIPT-Plus result, including 233 aneuploidies and 31 CNVs. 233 (88.26%) patients had invasive diagnostic testing and 136 results were confirmed as true positives, including 2 RATs and 15 CNVs.
• PPVs for RATs and CNVs were 6.67% and 51.72%, respectively.

Yuan X, Yong W, Dai L, Wang W, Wu L. Ann Transl Med. 2023;11(2):111. doi:10.21037/atm-22-6343. Open Access: Learn more

Tags: Clinical Experience / Clinical Utility, 2023, China, RAAs, CNVs

• Retrospective study of over 12,000 women who underwent NIPT / expanded NIPT (NIPT-Plus), including 111 cases of positive results.
• PPVs of NIPT/NIPT-Plus for microdeletion/microduplication syndrome (MMS) and RATs were 44.4% and 7.7%, respectively.
• Ultrasound findings of SCAs, MMS, and RATs were relatively mild and included normal findings, soft markers, fetal growth restriction, or polyhydramnios, and the ultrasound findings were similar between false positive and true positive cases.

Hong DK, Park JE, Kang KM, et al. Diagnostics (Basel). 2023;13(4):580. Published 2023 Feb 4. doi:10.3390/diagnostics13040580. Open Access: Learn more

Tags: Case Report / Case Series, 2023, South Korea, RAAs

• “Overall, six cases were diagnosed with RATs. There was a suspicion of trisomies of chromosomes 7, 8, and 15 in two cases each. However, these cases were confirmed to have a normal karyotype using amniocentesis. In one of six cases, PWS [Prader-Willi syndrome] caused by maternal UPD 15 was diagnosed using MS-PCR and MS-MLPA. We propose that in cases where RAT is detected by NIPT, UPD should be considered following trisomy rescue. Even if amniocentesis confirms a normal karyotype, UPD testing (such as MS-PCR and MS-MLPA) should be recommended for accurate assessment, as an accurate diagnosis can lead to appropriate genetic counseling and improved overall pregnancy management.”

Maya I, Salzer Sheelo L, Brabbing-Goldstein D, et al. Ultrasound Obstet Gynecol. 2023;61(6):698-704. doi:10.1002/uog.26177.

Tags: Clinical Experience / Clinical Utility, 2023, Israel, RAAs, CNVs

• “Conclusions: 5-NIPS and even genome-wide NIPS would miss 63.9% and 54.1% of clinically significant CMA findings [in pregnancies without major structural anomalies], respectively. The added value of 5-NIPS expanded to detect common microdeletions over 5-NIPS is about 0.035%, and the overall added value of genome-wide NIPS aimed at large CNVs is about 0.14%, both much lower compared with the added value of CMA (0.91%).”

Ma N, Zhu Z, Hu J, et al. Front Genet. 2023;14:1121121. Published 2023 Mar 10. doi:10.3389/fgene.2023.1121121. Open Access: Learn more

Tags: Case Report / Case Series, 2023, China, RAAs

• “The non-invasive prenatal testing (NIPT) results suggested trisomy 9 in two fetuses. Karyotype analysis of amniocytes showed a high level (42%-50%) of mosaicism, and chromosomal microarray analysis (CMA) of uncultured amniocytes showed no copy number variation (CNV) except for large fragment loss of heterozygosity. Ultrasound findings were unmarkable except for small for gestational age… The results [of molecular testing of fetal and placental tissue samples] confirmed the presence of true fetoplacental mosaicism with levels of trisomy 9 mosaicism from 76% to normal in various tissues.”

De Falco L, Vitiello G, Savarese G, et al. Genes (Basel). 2023;14(3):668. Published 2023 Mar 7. doi:10.3390/genes14030668. Open Access: Learn more

Tags: Case Report / Case Series, 2023, Italy, CNVs

• Case report of 44.1 Mb 4p dup detected by NIPT at 12 weeks. Amniocentesis was performed at 18 weeks; SNP (single nucleotide polymorphism) array found a de novo2 Mb deletion on chromosome 4 near the Wolf-Hirschhorn syndrome critical region and a normal 46,XY karyotype was identified by G-banding analysis.
• Studies of fetal and placental tissue confirmed presence of type VI true fetal mosaicism, with SNP array on 3 placental samples showing different results.

Zhang M, Tang J, Li J, et al. Eur J Obstet Gynecol Reprod Biol. 2023;284:5-11. doi:10.1016/j.ejogrb.2023.03.002. Open Access: Learn more

Tags: Clinical Experience / Clinical Utility, 2023, China, RAAs, CNVs

• “Results: NIPT detected 292 cases (0.36%) with rare autosomal abnormalities among the 81,518 cases sampled. Of these, 140 (0.17%) showed rare autosomal trisomies (RATs), and 102 of these patients agreed to undergo invasive testing. Five cases were true positives, with a positive predictive value (PPV) of 4.90%. Copy number variants (CNV) were detected in 152 samples of the total cases (0.19%), and 95 of the patients involved agreed to the use of CMA. Twenty-nine of these cases were confirmed to be true positive, with a PPV of 30.53%. Detailed follow-up information was obtained in 81 cases from 97 patients with false-positive results for RATs. Thirty-seven of these cases (45.68%) had adverse perinatal outcomes, with a higher incidence of small for gestational age (SGA), intrauterine growth retardation (IUGR), and preterm birth (PTB).”
• “Conclusions: NIPT is not recommended for screening for RATs. However, considering that positive results are associated with an increased risk of IUGR and PTB, additional fetal ultrasound examination should be performed to monitor fetal growth. In addition, NIPT has a reference value in screening for CNVs, especially pathogenic CNVs, but a comprehensive analysis of prenatal diagnosis combined with ultrasound and family history is still needed.”

Long S, O’Leary P, Dickinson JE. J Genet Couns. 2023;10.1002/jgc4.1715. doi:10.1002/jgc4.1715. Open Access: Learn more

Tags: Patient Perspectives, 2023, Australia, RAAs, CNVs

• 219 women in Western Australia were surveyed regarding the use of NIPT to detect multiple different single gene and chromosome conditions.
• Most women (96%) supported expanded NIPT for single gene and chromosome conditions as long as the test does not pose any risk to the pregnancy and can provide relevant medical information about the fetus. Most women (80%) indicated that expanded NIPT should be available at any stage during pregnancy and 68% indicated that the cost of the test would influence their participation in testing.

Talantova OE, Koltsova AS, Tikhonov AV, et al. Genes (Basel). 2023;14(4):913. Published 2023 Apr 14. doi:10.3390/genes14040913. Open Access: Learn more

Tags: Case Report / Case Series, 2023, Russia, RAAs

• Case report of a woman with a positive result for trisomy 2 by GW-NIPT following a negative targeted NIPT for common trisomies and subsequent abnormal ultrasounds at 13/14 and 16/17 weeks. Low-level true fetal mosaicism of trisomy 2 and multiple congenital anomalies were confirmed.

De Falco L, Savarese G, Savarese P, et al. Genes (Basel). 2023;14(5):982. Published 2023 Apr 26. doi:10.3390/genes14050982. Open Access: Learn more

Tags: Laboratory Performance / Laboratory Experience, 2023, Italy, RAAs, CNVs

• Cohort of 1,244 twin pregnancy samples undergoing NIPT, of which 61.5% chose GW-NIPT for RAAs and CNVs in addition to common trisomies.
• There were 29 high-risk results: 18 T21, one T18, 6 RAA, and 4 CNV cases. Clinical and diagnostic follow-up was available for 27/29 (93%) of these cases.
• Clinical follow-up was available for 96.6% of low-risk cases; all were true negatives.

Dubois ML, Winters PD, Rodrigue MA, Gekas J. Front Genet. 2023;14:976051. Published 2023 Apr 18. doi:10.3389/fgene.2023.976051 Open access: Learn more

Tags: Patient Perspectives, 2023, Canada, RAAs, CNVs

• 200 general-risk patients in Quebec were surveyed regarding their expectations for expanded NIPT.
• 88% wanted all information that could have an immediate impact on fetal health, 82% wanted all information that could have an immediate impact on infant health from birth, and almost half wanted information about RAAs and/or all genetic information that may affect the baby.

Chen CP, Ko TM, Chen SW, et al. Taiwan J Obstet Gynecol. 2023;62(3):457-460. doi:10.1016/j.tjog.2023.03.008. Open Access: Learn more

Tags: Case Report / Case Series, 2023, Taiwan, RAAs

• “We present low-level mosaic trisomy 9 at amniocentesis associated with a positive non-invasive prenatal testing (NIPT) for trisomy 9, maternal uniparental disomy (UPD) 9, intrauterine growth restriction (IUGR) and a favorable fetal outcome in a pregnancy.”

Scott F, Smet ME, Elhindi J, et al. Ultrasound Obstet Gynecol. 2023;10.1002/uog.26272. doi:10.1002/uog.26272

Tags: Clinical Experience / Clinical Utility, 2023, Australia, RAAs, CNVs

• Retrospective study of all cases with NIPT from 3 tertiary providers of obstetric ultrasound using NIPT as a first line screening test over a 4-year period.
• “The LTFU [late first trimester ultrasound] findings significantly altered the PPV of the NIPT result for trisomies 13, 18 and 21, monosomy X (MX) and rare autosomal trisomies (RATs), but not for the other sex chromosomal abnormalities or segmental imbalances (>7 Mb). An abnormal LFTU increased the PPV close to 100% for trisomies 13, 18 and 21, MX and RATs. The magnitude of the PPV alteration was highest for the lethal chromosomal abnormalities.”
• “Conclusions: LTFU after a high-risk NIPT result can alter the PPV of many chromosomal abnormalities, assisting counselling regarding invasive prenatal testing and pregnancy management.”

Zhang S, Zhou Y, Xiao G, Qiu X. Mol Genet Genomic Med. 2023;e2229. doi:10.1002/mgg3.2229 Open access: Learn more

Tags: Case Report / Case Series, 2023, China, RAAs, CNVs

• “Herein, we describe the clinical phenotypes and various prenatal diagnostic processes used for two rare cases of 9p duplication mosaicism [initially suspected based on NIPT results] and review the prior literature in the field to evaluate the merits of different methods for diagnosing mosaic 9p duplication.”
• “This study demonstrated the potential of using NIPT to suggest 9p duplication in early pregnancy.”

Zhu S, Jia C, Hao S, et al. Mol Genet Genomic Med. 2023;e2200. doi:10.1002/mgg3.2200 Open Access: Learn more

Tags: Clinical Experience / Clinical Utility, 2023, China, RAAs, CNVs

• Prospective study of over 25,000 pregnant women who had NIPS-PLUS. 415 individuals had positive results, including 275 indicating aneuploidy and 140 indicating microdeletion/microduplication syndromes (MMS).
• Following amniocentesis, 188 were confirmed as true positives (including 41 cases of RATs and 57 MMS).
• PPV was 25.63% for RATs, PPV was 44.66% for CNVs <5 Mb, PPV was 29.73% for CNVs >5 Mb.

Soster E, Tynan J, Gibbons C, et al. Mol Cytogenet. 2023;16(1):10. Published 2023 Jun 10. doi:10.1186/s13039-023-00642-4 Open Access: Learn more

Tags: Laboratory Performance / Laboratory Experience, 2023, United States, CNVs  

• Reviewed 701 high-risk pregnancies with both GW-NIPT and prenatal microarray.
• For aneuploidies, CNVs ≥7Mb, and select microdeletions, sensitivity was 93.8%, specificity was 97.3%, and PPV was 63.8%.
• “Conclusions: While microarray provides the most robust assessment of fetal CNVs, this study suggests that genome wide cfDNA can reliably screen for large CNVs in a high-risk cohort. Informed consent and adequate pretest counseling are essential to ensuring patients understand the benefits and limitations of all prenatal testing and screening options.”

Fiorentino D, Dar P.. Clin Obstet Gynecol. 2023;66(3):579-594. doi:10.1097/GRF.0000000000000799

Tags: Review / Meta-Analysis, 2023, International, RAAs, CNVs

• “Conclusion: To conclude, cfDNA is an attractive screening tool for chromosomal abnormalities that otherwise do not have dedicated screening modalities. However, the expansion of routine prenatal genetic screening to include rare syndromes has to balance patients’ desire for information about their pregnancy and the clinical utility of a screening test. Unfortunately, for many CNVs and RAAs, the clinical utility of this screening remains unclear. The principle of patient autonomy would dictate that these commercially available tests not be withheld from patients who desire greater information regarding their pregnancy, but detailed counseling is needed to ensure that the benefits and limitations of expanded cfDNA are clearly understood.”