Non-Invasive Prenatal Testing for Fetal Aneuploidy (Powered by Constellation)

NIPT Overview

2007537 Non-Invasive Prenatal Testing for Fetal Aneuploidy

ARUP offers non-invasive prenatal testing (NIPT) as early as 9 weeks gestation to help manage your patient’s pregnancy. Maternal blood is used to screen for specific chromosomal aneuploidies in the fetus, and results are reported as either "low risk" or "high risk" based on internal risk scores. In addition, each patient report includes interpretive comments carefully drafted by ARUP medical directors and genetic counselors. In rare cases, a specimen may not pass quality metrics or fall outside the limitation of the algorithm, and a result may not be provided. Specific guidance will be provided in such cases. For a "high risk" result, the likelihood of the fetus actually being affected (based on published or internal data) will be provided to help you and your patient decide on next steps. As NIPT is a screening test and is not diagnostic for the conditions reported, any patient with a result indicating a potential abnormality should be offered confirmatory invasive testing via amniocentesis or CVS, or testing of the baby after delivery.1

What is reported in ARUP's NIPT?

The risks for:
  • Trisomy 21 (Down syndrome)
  • Trisomy 18
  • Trisomy 13
  • Triploidy/vanishing twin
  • Sex chromosome aneuploidies:
    • Monosomy X (Turner syndrome)
    • XXX (Triple X syndrome)
    • XXY (Klinefelter syndrome)
    • XYY
Also included are:
  • Fetal fraction (%)
  • Fetal sex (patient may opt out)

How does ARUP's NIPT perform?

In a cross-validation study, ARUP's NIPT was completely concordant with results generated by Natera's Panorama. Like Panorama, ARUP's NIPT has the ability to distinguish between fetal and maternal DNA in the mother’s blood, and to detect aneuploidies in fetal fractions as low as 3%. As for concordance with clinical outcome, ARUP's NIPT was found to be >99% accurate for aneuploidies and fetal sex determination.2 NIPT is performed at ARUP's genomics laboratory using multiplexed single-nucleotide polymorphism (SNP) analysis and massively parallel sequencing. Data are uploaded to Natera’s Constellation (a cloud-based general-purpose copy number analysis software) that facilitates interpretation by ARUP's medical directors and genetic counselors. By eliminating the extra transport to Natera, sample integrity and turn-around time are improved.

  ARUP Validation Data PPV*
Agreement with Panorama Concordance with Clinical Outcome
Low Risk (negative) 100% (146/146) 98.3% (58/59)** NA
Trisomy 21 100% (18/18) >99% (11/11) 91%3
Trisomy 18 100% (9/9) >99% (3/3) 93%3
Trisomy 13 100% (5/5) >99% (1/1) 38%3
Monosomy X 100% (8/8) >99% (1/1) 50%3
Sex chromosome trisomy (XXX, XXY, XYY) 100% (11/11) NA (0/0) 54% (XXX); 63% (XXY); 88% (XYY)4
Triploidy or twin 100% (4/4) >99% (9/9) No data
Fetal Sex 100% (99/99) >99% (73/73) 100% 3

* PPV (positive predictive value) indicates the percentage of pregnancies that were classified as high risk by NIPT and were found to actually have the aneuploidy based on published or internal data.
** One sample, which was 46,XY (normal male) by karyotype on amniocytes, exhibited a distinct pattern of XXY, suggesting a possible difference between placental DNA found in plasma and the actual fetal DNA. Independent review by Natera also called this case XXY.

1. Gregg A et al. Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics. Genet Med. 2016; 1056-65. PMID: 27467454

2. ARUP Whitepaper: Noninvasive prenatal testing for fetal aneuploidy, Powered by Natera’s Constellation, results to date as of November 2016

3. Dar P et al. Clinical experience and follow-up with large scale single-nucleotide polymorphism-based non-invasive prenatal aneuploidy testing. Am J Obstet Gynecol 2014; 211(5):527e1-527 e17. PMID: 25111587

4. ARUP historical data

NIPT with Microdeletions

2010232 Non-Invasive Prenatal Testing for Fetal Aneuploidy with Microdeletions

2013142 Non-Invasive Prenatal Testing for Fetal Aneuploidy with 22q11.2 Microdeletion

A small, missing (“deleted”) piece of a chromosome is called a microdeletion. Unlike aneuploidies, such as Down syndrome, which occur more frequently in older mothers, microdeletions can occur in pregnancies of younger mothers at the same rate as they do in older mothers. As a group, they happen in a random fashion at a frequency of 1 in 1,000 pregnancies.

Five microdeletions, all of which can be associated with serious health issues, can be screened for (in addition to aneuploidies in the basic NIPT screen). Two ordering options are available:

Orderable tests Aneuploidies screened Microdeletion syndromes screened
DiGeorge (22q11.2) Prader-Willi Angelman 1p36 Cri-du-chat
2010232 T21, T18, T13, MX Yes Yes Yes Yes Yes
2013142 T21, T18, T13, MX Yes No No No No

How does ARUP's Microdeletion test perform?

In a cross-validation study, ARUP's microdeletion test was >99% concordant with results generated by Natera. Like Natera's test, ARUP's microdeletion test has the ability to distinguish between fetal and maternal DNA in the mother’s blood, and assess whether the fetal DNA inherited from the mother or the father is missing at disease-causing genetic regions in the fetus. As for concordance with clinical outcome, ARUP's microdeletion test was found to be 95% accurate for each genetic region that was assessed. This was a small sample set, and more data will be collected with time. The NIPT microdeletion test is performed at ARUP's genomics laboratory using multiplexed single-nucleotide polymorphism (SNP) analysis and massively parallel sequencing. Data are uploaded to Natera’s Constellation (a cloud-based general-purpose copy number analysis software) that facilitates interpretation by ARUP's medical directors and genetic counselors.

  ARUP Validation Data
(number of allele assessmentsa)
PPV*
Agreement with
Natera
Concordance with
Clinical Outcome
Combined Microdeletions >99% (981/984) 95% (38/40) 40%3e
DiGeorge (22q11.2)b >99% (244/246) >90% (10/10) 20%2
Prader-Willi / Angelmanc >99% (245/246) 90% (9/10) 4 - 5%1
1p36d 100% (246/246) 90% (9/10) 17%1
Cri-du-chat (5p-) 100% (246/246) >90% (10/10) 5%1

* PPV (positive predictive value) indicates the percentage of pregnancies that were classified as high risk by the screen and were found to actually have a fetus with the microdeletion, based on published data (see references below).
aTwo assessments were made for each microdeletion region to determine whether the maternally inherited or the paternally inherited alleles were missing. Each sample was tested for 8 allele assessments.
bIn two cases, ARUP and Natera's assessments for the 22q11.2 (DiGeorge) region were discordant. Natera designated one case as high risk for the deletion of the maternal allele, while ARUP called this low risk after a reflex protocol (Ref 3 below). The second case was also called low risk by ARUP but high risk by Natera for the paternal deletion of 22q11.2. Regions of homozygosity on multiple chromosomal regions were observed in this sample, complicating the analysis. No clinical outcomes were available for these two cases.
cOne case was called low risk by ARUP for Angelman syndrome after a reflex protocol (Ref 3 below), while Natera called it high risk. No clinical outcome is available for this case. One case was called high risk for Prader-Willi syndrome by both ARUP and Natera, but the fetus was later found to be normal (negative for Prader-Willi syndrome).
dOne case was called high risk for the deletion of the maternal allele of 1p36 by both ARUP and Natera. The fetus, however, was later found to be normal (negative for 1p36 deletion syndrome).
eThe overall PPV listed here is from the latest data in Ref 3. In this study, the PPV for the individual regions were higher than listed in this table.

1. Wapner RJ, Babiarz JE, Levy B, Stosic M et al. Expanding the scope of noninvasive prenatal testing: detection of fetal microdeletion syndromes. Am J Obstet Gynecol. 2015 Mar;212(3):332.e1-9. PMID: 25479548

2. Ryan A, Iyengar S, Jiorle B et al. Raising the confidence threshold increases the positive predictive value of a SNP-based NIPT for the 22q11.2 microdeletion. Eur J Hum Genet. 2016 May;24-E-supplement 1:53 [meeting abstract P01.002]

3. Kalyan A et al. Performance of a SNP-based NIPT in screening for five clinically significant microdeletions in a large clinical cohort. International Society for Prenatal Diagnosis (ISPD). 20th International Conference on Prenatal Diagnosis and Therapy. July 10–13, 2016. Berlin, Germany [meeting abstract P-192]

Frequently Asked Questions

Can microdeletions be ordered alone?
No, screening for aneuploidies (T21, T18, T13, MX), and fetal sex will always be performed in addition to microdeletion screening.
What are the cytogenetic and genomic coverages of microdeletions tested?
  Cytogenetic loci Genomic coverage
DiGeorge syndrome 22q11.2 2.91 Mb
Prader-Willi/Angelman syndromes 15q11.2 - q13.1 5.85 Mb
1p36 microdeletion syndrome 1p36.22 - p36.33 10.0 Mb
Cri-du-chat syndrome 5p14.3 - p15.33 20.0 Mb
How large does the microdeletion need to be to be detected by this screen?
In order to be assessed as "high risk", at least 87% to 94% of the covered region listed above has to be deleted, depending on the disorder. This approach keeps the number of false positives low. Smaller deletions are not typically reported.

Twins/Egg Donors (Panorama - performed at Natera)

In continued collaboration with Natera, ARUP Laboratories is able to offer NIPT for twin pregnancies, as well as for singleton egg donor or surrogate pregnancies by forwarding such specimens to Natera for testing. In an effort to make this as seamless as possible for providers and clients, twin/donor pregnancy specimens may be sent to ARUP using the same test codes and processes as for regular singleton pregnancies.

Please clearly mark "twin" (including chorionicity if known), "egg donor", or "surrogate" on the patient history form when submitting the patient specimen, and ARUP will forward the specimen to Natera for testing.

What is reported?

Elements Reported Monozygotic twins Dizygotic twins Egg donor and surrogate
Trisomy 21 (T21) Yes Yes Yes
Trisomy 18 (T13) Yes Yes Yes
Trisomy 13 (T18) Yes Yes Yes
Monosomy X (Turner) Yes No No
Sex chromosome trisomies (reported when identified) Yes No No
Triploidy No No No
Microdeletions
22q11.2 microdeletion Yes No No
Extended microdeletion panel No No No
Other
Fetal Fraction (%) Combined value Values for each twin One value
Fetal sex of both twins
(patient may opt out)
Yes Yes Yes
Twin zygosity Monozygotic Dizygotic NA

Frequently Asked Questions

What test code should be ordered for twin or egg donor/surrogate pregnancies?
You may use the same test codes as you would for a singleton pregnancy. Please note that the full panel of microdeletions is not available for twin or egg donor/surrogate pregnancies.

  • Please use test code 2007537 for the basic NIPT (cfDNA) screen for trisomies 13, 18, 21, monosomy X and fetal sex.

  • Please use test code 2013142 for the basic NIPT screen plus the 22q microdeletion (DiGeorge / Velocardiofacial syndrome) for known monozygotic (identical) twin pregnancies. This test is not available for dizygotic (non-identical) twin gestations or for pregnancies achieved using a donor egg or a surrogate.
Can microdeletions be tested on twins or egg donor/surrogate pregnancies?
The full panel of microdeletions is only available for singleton gestations derived from the patient's own egg. The 22q11.2 microdeletion may be tested in singleton and monozygotic (identical) twin cases only. Dizygotic twins and egg donor/surrogate pregnancies cannot be tested for any of the microdeletions.
Can twin pregnancies resulting from an egg donor be tested?
No. The combination of twins and egg donor in a same pregnancy is currently outside of the scope of the test.
What if the mother has had a bone marrow transplant?
The test is not validated for a mother who has had an allogenic (from a donor) bone marrow transplant recipient, whether for a singleton or a twin pregnancy. Patients who have had a bone marrow transplant using their own stem cells may be tested using this technology.
What is the sensitivity / specificity of the twin test?
Specificity and sensitivity of this test is >99% based on Natera's internal study involving 100+ specimens with known clinical outcomes for aneuploid/euploid, zygosity, and fetal genders.

Patient Chart Examples

Twins - Monozygotic Twins - Dizygotic Singleton - Egg donor and surrogate pregnancies

The Panorama test was developed by Natera, Inc. a laboratory certified under the Clinical Laboratory Improvement Amendments (CLIA). This test has not been cleared or approved by the U.S. Food and Drug Administration (FDA). Although FDA does not currently clear or approve laboratory-developed tests in the U.S., certification of the laboratory is required under CLIA to ensure the quality and validity of the tests.

Experts

Medical Directors

Yuan Ji, PhD
Medical Director, Molecular Genetics and Genomics
Allen N. Lamb, PhD
Section Chief, Cytogenetics and Genomic Microarray
Reha Toydemir, MD, PhD, FACMG
Medical Director, Cytogenetics and Genomic Microarray

Genetic Counselors

Shelly Bosworth, MS, LCGC
Phone: (800) 242-2787, ext. 3195
Danielle LaGrave, MS, LCGC
Phone: (800) 242-2787, ext. 2020
Amanda Openshaw, MS, LCGC
Phone: (800) 242-2787, ext. 3429

Additional Resources

ARUP Links

ARUP Genetics
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