Expanding the scope of noninvasive prenatal testing: detection of fetal microdeletion syndromes

Wapner, Ronald J.; Babiarz, Joshua E.; Levy, Brynn; Stosic, Melissa; Zimmermann, Bernhard; Sigurjonsson, Styrmir; Wayham, Nicholas; Ryan, Allison; Banjevic, Milena; Lacroute, Phil; Hu, Jing; Hall, Megan P.; Demko, Zachary; Siddiqui, Asim; Rabinowitz, Matthew; Gross, Susan J.; Hill, Matthew D.; Benn, Peter

doi:10.1016/j.ajog.2014.11.041

Cited by 279 publications

(308 citation statements)

References 32 publications

(39 reference statements)

Supporting

Mentioning

291

Contrasting

Unclassified

Order By: Relevance

“…Therefore, PPV and NPV have been modeled. [63][64][65] One report showed that for a specific combination of CNVs studied, PPV ranged from 3.8 to 17%. In a large retrospective study of more than 21,000 samples, the aggregate PPV for several CNVs screened simultaneously was 18% (specific conditions: 11-48%).…”

Section: Acmg Statement Should Nips Be Offered For Detection Of Copy mentioning

confidence: 99%

Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics

Gregg

Skotko

Benkendorf

et al. 2016

Genetics in Medicine

583

560

View full text Add to dashboard Cite

guidelines and statements have assisted patients seeking prenatal screening information and health-care providers responsible for providing accurate and up-to-date information to their patients. [1][2][3] Until recently, noninvasive prenatal screening for aneuploidy relied on measurements of maternal serum analytes and/or ultrasonography. These have a false-positive rate of approximately 5% and detection rates of 50-95%, depending on the specific screening strategy used. Advances in genomic technologies led to noninvasive prenatal screening that relies on the presence of cell-free DNA derived from the placenta but circulating in maternal blood, which is referred to here as noninvasive prenatal screening (NIPS). Massive parallel sequencing of maternal and placental (also called fetal when speaking of the fraction of this DNA in maternal blood) fragments of DNA occurs simultaneously. Sequencing with quantification can be random, targeted, and followed by quantification or exploitation of single-nucleotide polymorphisms. [4][5][6][7][8] Alternatively, sequencing can take place by measuring the release of hydrogen ions as nucleotides are added to a DNA template (i.e., semiconductor sequencing). 9 Microarray technology can also be used to quantify DNA. 10 Bioinformatics that enable these methodologies is complex and proprietary. Since the introduction of NIPS in 2011, health-care providers and patients have experienced marketing pressures, rapidly evolving professional practice guidelines, and confusion regarding the appropriate role of Noninvasive prenatal screening using cell-free DNA (NIPS) has been rapidly integrated into prenatal care since the initial American College of Medical Genetics and Genomics (ACMG) statement in 2013. New evidence strongly suggests that NIPS can replace conventional screening for Patau, Edwards, and Down syndromes across the maternal age spectrum, for a continuum of gestational age beginning at 9-10 weeks, and for patients who are not significantly obese. This statement sets forth a new framework for NIPS that is supported by information from validation and clinical utility studies. Pretest counseling for NIPS remains crucial; however, it needs to go beyond discussions of Patau, Edwards, and Down syndromes. The use of NIPS to include sex chromosome aneuploidy screening and screening for selected copy-number variants (CNVs) is becoming commonplace because there are no other screening options to identify these conditions. Providers should have a more thorough understanding of patient preferences and be able to educate about the current drawbacks of NIPS across the prenatal screening spectrum. Laboratories are encouraged to meet the needs of providers and their patients by delivering meaningful screening reports and to engage in education. With health-care-provider guidance, the patient should be able to make an educated decision about the current use of NIPS and the ramifications of a positive, negative, or no-call result. Genet Med advance online publication 28 July 2016Key Words: cell-f...

show abstract

Section: Acmg Statement Should Nips Be Offered For Detection Of Copy mentioning

confidence: 99%

Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics

Gregg

Skotko

Benkendorf

et al. 2016

Genetics in Medicine

583

560

View full text Add to dashboard Cite

show abstract

“…13 Until now, NIPT of subchromosomal abnormalities has been reported only in a small number of cases of affected pregnancies, although a larger series using spiked samples has been reported. 16 The lack of data makes it difficult to accurately determine the test sensitivity and specificity and, more importantly, the positive and negative predictive values, which are crucial if this is to be implemented in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

“…Algorithms for detecting subchromosomal abnormalities can be categorized into two main groups: the targeted approach, which looks for abnormalities in known locations, 15,16 and the whole-genome approach, which can be applied in situations where the location and size of the fetal CNVs are not known 13,14 and where read counts higher or lower than those of the reference set can indicate the presence of CNVs. Here, we present results for a series of maternal plasma samples from pregnancies with known subchromosomal abnormalities occurring across the genome and explore the potential for routine implementation.…”

Section: Introductionmentioning

confidence: 99%

Limited Clinical Utility of Non-invasive Prenatal Testing for Subchromosomal Abnormalities

Karampetsou

Boustred

et al. 2016

Obstetrical &Amp; Gynecological Survey

View full text Add to dashboard Cite

The use of massively parallel sequencing of maternal cfDNA for non-invasive prenatal testing (NIPT) of aneuploidy is widely available. Recently, the scope of testing has increased to include selected subchromosomal abnormalities, but the number of samples reported has been small. We developed a calling pipeline based on a segmentation algorithm for the detection of these rearrangements in maternal plasma. The same read depth used in our standard pipeline for aneuploidy NIPT detected 15/18 (83%) samples with pathogenic rearrangements > 6 Mb but only 2/10 samples with rearrangements < 6 Mb, unless they were maternally inherited. There were two false-positive calls in 534 samples with no known subchromosomal abnormalities (specificity 99.6%). Using higher read depths, we detected 29/31 fetal subchromosomal abnormalities, including the three samples with maternally inherited microduplications. We conclude that test sensitivity is a function of the fetal fraction, read depth, and size of the fetal CNV and that at least one of the two false negatives is due to a low fetal fraction. The lack of an independent method for determining fetal fraction, especially for female fetuses, leads to uncertainty in test sensitivity, which currently has implications for this technique's future as a clinical diagnostic test. Furthermore, to be effective, NIPT must be able to detect chromosomal rearrangements across the whole genome for a very low false-positive rate. Because standard NIPT can only detect the majority of larger (>6 Mb) chromosomal rearrangements and requires knowledge of fetal fraction, we consider that it is not yet ready for routine clinical implementation.

show abstract

“…Peripheral blood specimens were collected and sent by 2-day air transportation to the Natera laboratory without plasma separation prior to shipment. Laboratory procedures were as described elsewhere [7,11,[15][16][17][18][19][20]. Following the NIPS analyses, all patient reports were communicated electronically to Echevarne and to the individual referring physicians and clinics.…”

Section: Methodsmentioning

confidence: 99%

A National Referral Laboratory’s Experience with the Implementation of SNP-Based Non-invasive Prenatal Screening for Fetal Aneuploidy and Select Microdeletion Syndromes

Santamaría¹,

Bermejo²,

Cigarrán³

et al. 2018

Journal of Fetal Medicine

Self Cite

View full text Add to dashboard Cite

To retrospectively evaluate the successful test rate and performance of non-invasive prenatal screening (NIPS) for aneuploidies and microdeletions with international transportation of samples. Blood samples from Iberian women with singleton pregnancies were sent to a US laboratory for NIPS for aneuploidy and microdeletion syndromes (22q11.2, 1p36, Cri-du-chat, Prader Willi and Angelman). The NIPS methodology involved the analysis of single nucleotide polymorphisms in cell-free DNA in maternal plasma. Women with high-risk results were offered karyotyping and/or microarray confirmatory studies. Based on 14,175 women with successful testing (98.76% of all referrals), the overall test positive rate was 2.37% (1.9% for aneuploidy and 0.47% for microdeletion syndromes). Based on cases with known outcome, the positive predictive values (PPVs) were: for trisomy 21, 98.6%; trisomy 18, 85.7%; trisomy 13, 71.4%; monosomy-X, 87.5%; other sex chromosome aneuploidies, 100%; 22q11.2 deletion, 15.4%; and other microdeletions combined, 20%. With a protocol change that involved selective use of resequencing at a higher depth of read, the PPV for 22q11.2 deletion increased to 33.3 and 75% for the other microdeletions. Effective NIPS for both aneuploidies and select microdeletion syndromes can be provided even when this involves international transportation of blood specimens.

show abstract

Expanding the scope of noninvasive prenatal testing: detection of fetal microdeletion syndromes

Abstract: SNP-based noninvasive prenatal microdeletion screening is highly accurate. Because clinically relevant microdeletions and duplications occur in >1% of pregnancies, regardless of maternal age, noninvasive screening for the general pregnant population should be considered.

Cited by 279 publications

References 32 publications

Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics

Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics

Limited Clinical Utility of Non-invasive Prenatal Testing for Subchromosomal Abnormalities

A National Referral Laboratory’s Experience with the Implementation of SNP-Based Non-invasive Prenatal Screening for Fetal Aneuploidy and Select Microdeletion Syndromes

Contact Info

Product

Resources

About