Noninvasive Prenatal Testing and Incidental Detection of Occult Maternal Malignancies

Bianchi, Diana W.; Chudova, Darya; Sehnert, Amy J.; Bhatt, Sucheta; Murray, Kathryn; Prosen, Tracy L.; Garber, Judy E.; Wilkins‐Haug, Louise; Vora, Neeta L.; Warsof, Steven L.; Goldberg, James D.; Ziainia, Tina; Halks-Miller, Meredith

doi:10.1097/01.ogx.0000473791.14913.b7

Cited by 68 publications

(105 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In prenatal diagnostics, samples obtained from chorionic villi could be analyzed for mosaic karyotypes or maternal contamination. Furthermore, many different cancers have been associated with copy number changes that could potentially be detected from serum cfDNA or a solid tumor sample that contains both normal and cancer cells (25,26). Because the cost of next generation sequencing continues to drop, we expect that this technique will become applicable for a broad range of diseases.…”

Section: Discussionmentioning

confidence: 99%

Noninvasive detection of fetal subchromosomal abnormalities by semiconductor sequencing of maternal plasma DNA

Yin

Peng

Zhao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

100

124

View full text Add to dashboard Cite

Noninvasive prenatal testing (NIPT) using sequencing of fetal cellfree DNA from maternal plasma has enabled accurate prenatal diagnosis of aneuploidy and become increasingly accepted in clinical practice. We investigated whether NIPT using semiconductor sequencing platform (SSP) could reliably detect subchromosomal deletions/duplications in women carrying high-risk fetuses. We first showed that increasing concentration of abnormal DNA and sequencing depth improved detection. Subsequently, we analyzed plasma from 1,456 pregnant women to develop a method for estimating fetal DNA concentration based on the size distribution of DNA fragments. Finally, we collected plasma from 1,476 pregnant women with fetal structural abnormalities detected on ultrasound who also underwent an invasive diagnostic procedure. We used SSP of maternal plasma DNA to detect subchromosomal abnormalities and validated our results with array comparative genomic hybridization (aCGH). With 3.5 million reads, SSP detected 56 of 78 (71.8%) subchromosomal abnormalities detected by aCGH. With increased sequencing depth up to 10 million reads and restriction of the size of abnormalities to more than 1 Mb, sensitivity improved to 69 of 73 (94.5%). Of 55 false-positive samples, 35 were caused by deletions/ duplications present in maternal DNA, indicating the necessity of a validation test to exclude maternal karyotype abnormalities. This study shows that detection of fetal subchromosomal abnormalities is a viable extension of NIPT based on SSP. Although we focused on the application of cell-free DNA sequencing for NIPT, we believe that this method has broader applications for genetic diagnosis, such as analysis of circulating tumor DNA for detection of cancer.noninvasive prenatal testing | NIPT | maternal plasma DNA | cell-free DNA | semiconductor sequencing G enomic disorders are defined by loss, gain, or translocation of chromosomal material. Deletion/duplication syndromes are known to be associated with a wide range of structural and functional abnormalities (1), such as Cri du Chat Syndrome (5p deletion) (2) and DiGeorge Syndrome (22q11.2 deletion) (3). Such deletion/duplication syndromes can be reliably diagnosed prenatally from the DNA of fetal cells; fetal DNA may be assessed for chromosomal abnormalities by karyotyping, FISH, comparative genomic hybridization (CGH), and array-based technologies (4). G-banded karyotyping is the predominant technique for diagnosis of chromosomal abnormalities, but it is limited to resolution of 5-10 Mb (5, 6). Genomic disorders of a smaller size are more reliably detected by chromosomal microarray analysis (CMA), of which array CGH (aCGH) is an example.According to The American Society of Human Genetics, CMA has replaced the standard metaphase karyotype in postnatal assessment of individuals with developmental delay, intellectual disability, congenital anomalies, and autism (7). In December of 2013, The American Congress of Obstetricians and Gynecologists and the Society of Maternal Fetal-Medicine recommended pr...

show abstract

Section: Discussionmentioning

confidence: 99%

Noninvasive detection of fetal subchromosomal abnormalities by semiconductor sequencing of maternal plasma DNA

Yin

Peng

Zhao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

100

124

View full text Add to dashboard Cite

show abstract

“…10,17 False positive cfDNA results have been demonstrated due to confined placental mosaicism (CPM), maternal low-level mosaicism, twin demise and rarely, maternal cancer. [18][19][20][21] All patients with positive cfDNA were offered prenatal diagnostic testing, and almost two-thirds of women had either a CVS or amniocentesis. In singletons with positive cfDNA for autosomal trisomy and either abnormal or unknown karyotype, the rate of termination was 67%.…”

Section: Discussionmentioning

confidence: 99%

Patient choice and clinical outcomes following positive noninvasive prenatal screening for aneuploidy with cell-free DNA (cfDNA)

et al. 2016

Self Cite

View full text Add to dashboard Cite

Objective Evaluate patient choices and outcomes following positive cfDNA.Method Retrospective cohort study of women with positive cfDNA through two academic centers between March 2012 and December 2014. Patients were screened based on ACOG indications. Medical records reviewed for counseling, ultrasound findings, diagnostic testing, karyotype and outcome.Results CfDNA was positive in 114 women; 105 singletons and 9 twin pairs. CfDNA was positive for autosomal trisomy (21, 18, 13) in 96 (84.2%) and sex chromosome aneuploidy in 18 (15.8%). Certified genetic counselors performed 95% of post-cfDNA counseling. Prenatal diagnostic testing was pursued by 71/114 (62%). Karyotype was available in 91/105 (86.7%) singletons and confirmed aneuploidy in 75/91 (82.4%); the PPV of cfDNA with any ultrasound finding was 93.6% versus 58.6% without a finding. An abnormal sonographic finding was seen in 4/16 (25%) singletons with false positive cfDNA. Fetal termination occurred in 53/79 (67%) singletons and 3/5 (60%) twins with prenatal abnormal or unknown karyotype for autosomal trisomy. Eleven fetuses (11/56, 19.6%) were terminated for suspected autosomal trisomy without karyotype confirmation.Conclusion Patient choices following positive cfDNA are varied. Ultrasound modifies the PPV of cfDNA. Termination rates for aneuploidy are not higher than historical controls. Recommendation for karyotype confirmation prior to termination is not universally followed.

show abstract

“…An array of other scholars have reflected on the social and ethical issues associated with NIPT in more detail and nuance than is possible here [5][6][7][8][23][24][25][26][27][28][29][30][31][32][33]. We direct the reader to these excellent resources for further information.…”

Section: The Future Landscape Of Prenatal Screening: Social and Ethicmentioning

confidence: 99%

“…Because NIPT, in particular, has the potential to detect many different conditions and genetic variations, some argue that concerns about its "eugenic potential" may be particularly acute [6][7][8]. That said, we focus this commentary on screening for Down syndrome (the reasons for which we offer later).…”

Section: Introductionmentioning

confidence: 99%

Keeping the Backdoor to Eugenics Ajar?: Disability and the Future of Prenatal Screening

Thomas

Rothman

2016

AMA Journal of Ethics

View full text Add to dashboard Cite

Noninvasive Prenatal Testing and Incidental Detection of Occult Maternal Malignancies

Cited by 68 publications

References 0 publications

Noninvasive detection of fetal subchromosomal abnormalities by semiconductor sequencing of maternal plasma DNA

Noninvasive detection of fetal subchromosomal abnormalities by semiconductor sequencing of maternal plasma DNA

Patient choice and clinical outcomes following positive noninvasive prenatal screening for aneuploidy with cell-free DNA (cfDNA)

Keeping the Backdoor to Eugenics Ajar?: Disability and the Future of Prenatal Screening

Contact Info

Product

Resources

About