SNP-based Microdeletion and Aneuploidy RegisTry
| Registry | NCT02381457, acronym SMART |
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| Status | Completed |
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| Study type | Observational |
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| Enrollment | 20960 (Actual) |
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| Sponsor | Natera, Inc. (Industry); collaborators: George Washington University, University of California, San Francisco, Montefiore Medical Center, Children's Hospital of Philadelphia |
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| Conditions | 22q11 Deletion Syndrome, DiGeorge Syndrome, Trisomy 21, Trisomy 18, Trisomy 13, Monosomy X, Sex Chromosome Abnormalities, Cri-du-Chat Syndrome, Angelman Syndrome, Prader-Willi Syndrome, 1p36 Deletion Syndrome |
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| Dates | start 2015-04-01, primary completion 2020-06-01, completion 2020-06-01, first posted 2015-03-06, last updated 2021-01-29 |
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| Locations | 21 sites in United States, Australia, Ireland, Spain, Sweden, United Kingdom |
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Related Papers Related Patents Related Grants Related Experts
All trials for 22q11 Deletion Syndrome All trials for DiGeorge Syndrome
-Summary
This multi-center prospective observational study is designed to track birth outcomes and perinatal correlates to the Panorama prenatal screening test in the general population among ten thousand women who present clinically and elect Panorama microdeletion and aneuploidy screening as part of their routine care. The primary objective is to evaluate the performance of Single Nucleotide Polymorphism (SNP)-based Non Invasive Prenatal Testing (NIPT) for 22q11.2 microdeletion (DiGeorge syndrome) in this large cohort of pregnant women. This will be done by performing a review of perinatal medical records and obtaining biospecimens after birth to perform genetic diagnostic testing for 22q11.2 deletion. Results from the follow-up specimens will be compared to those obtained by the Panorama screening test to determine test performance. Specific test performance parameters will include: PPV, specificity, and sensitivity.
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+Detailed description
The primary objective is to determine in a prospective study the performance of SNP based NIPT for the 22q11.2 microdeletion (DiGeorge syndrome) in a large cohort of pregnant women clinically opting for this form of screening. Specific test performance parameters will include: positive predictive value (PPV), specificity, and sensitivity.
Secondary objectives include:
1. Determine the test performance (PPV, specificity) of SNP based NIPT for detecting other microdeletion syndromes available in the Panorama microdeletion panel (e.g., 1p36 deletion, Cri-du-chat, Prader-Willi, and Angelman) individually and all combined (including 22q11.2). Given the incidences of <1:5000, the confidence intervals are expected to be large.
2. Determine the failure ('no call') rate for the Next-generation Aneuploidy Test Using SNPs (NATUS) method for 22q11.2 detection, as well as for aneuploidy.
3. Determine whether a more precise risk for aneuploidy can be generated in the setting of low fetal fraction by incorporating maternal BMI (adjusted fetal fraction percentile).
4. Assess whether low fetal fraction is associated with specific ultrasound findings that may indicate aneuploidy (e.g. triploidy, trisomy 13 and 18).
5. Investigate the relationship between NIPT and sonographic (nuchal translucency and anatomy survey) markers and serum markers from 1st and 2nd trimester aneuploidy screening.
6. Determine sensitivity, specificity, and PPV for chromosomal aneuploidies and sex chromosome abnormalities.
7. Perform detailed assessment of false positive aneuploidy samples to better understand sources of error, including placental studies to further refine issues surrounding mosaicism as NIPT represents circulating placental DNA.
8. Investigate any relationships between circulating placental DNA (fetal fraction) or other test parameters including potential genotypic markers, and outcomes related to abnormal placentation (including but not limited to preeclampsia, small for gestational age and morbidly adherent placenta).
9. Investigate other risk factors that may impact risk assessment for microdeletions including sonographic findings consistent with 22q11.2 (cardiac anomalies and thymus size).
+Arms and interventions
| Arm | Type | Interventions | Description |
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| Pregnancies undergoing prenatal microdeletion screening | | | Pregnant women undergoing non-invasive prenatal screening for microdeletion and aneuploidy syndromes.
No drug will be administrated, this cohort will undergo a non invasive prenatal blood test and then follow up data and specimens will be collected for research analysis. |
+Outcome measures
Primary outcomes
- 22q11.2 Snp-based non-invasive prenatal screening test performance, including positive predictive value (PPV), specificity, and sensitivity [3 years]: To determine in a prospective study the performance of SNP based NIPT for the 22q11.2 microdeletion (DiGeorge syndrome) in a large cohort of pregnant women clinically opting for this form of screening.
Secondary outcomes
- Combined microdeletion syndrome screening test performance [3 years]: Determine the test performance (PPV, specificity) of SNP based NIPT for detecting other microdeletion syndromes available in the Panorama microdeletion panel (e.g., 1p36 deletion, Cri-du-chat, Prader-Willi, and Angelman) individually and all combined (including 22q11.2). Given the incidences of <1:5000, the confidence intervals are expected to be large.
- No call rate [3 years]: Determine the failure ('no call') rate for the NATUS method for 22q11.2 detection, as well as for aneuploidy.
- Low fetal fraction aneuploidy risk refinement [3 years]: Determine whether a more precise risk for aneuploidy can be generated in the setting of low fetal fraction by incorporating maternal BMI (adjusted fetal fraction percentile), or whether low fetal fraction is associated with specific ultrasound findings that may indicate aneuploidy (e.g. triploidy, trisomy 13 and 18).
- Placental mosaicism exploration [3 years]: Perform detailed assessment of false positive aneuploidy samples to better understand sources of error, including placental studies to further refine issues surrounding mosaicism as NIPT represents circulating placental DNA.
- Placental complications exploration [3 years]: Investigate any relationships between circulating placental DNA (fetal fraction) or other test parameters including potential genotypic markers, and outcomes related to abnormal placentation (including but not limited to preeclampsia, small for gestational age and morbidly adherent placenta).
+Eligibility
Sex: Female, ages: 18 Years to 48 Years, accepts healthy volunteers
Inclusion Criteria:
* Singleton pregnancy
* Receiving Panorama prenatal screening test for both microdeletions (at least 22q11.2) and aneuploidy
* Planned hospital delivery
* Gestational age of ≥ 9 weeks, 0 days based on clinical information and evaluation.
* Able to provide informed consent
Exclusion Criteria:
* Received results of the Panorama test prior to enrollment
* Organ transplant recipient
* Egg donor used
+Locations (21)
| Facility | City | Country | Status |
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| University of California, San Francisco | San Francisco, California | United States | |
| Cooper University Hospital | Camden, New Jersey | United States | |
| Virtua | Mount Laurel, New Jersey | United States | |
| St. Peter's University | New Brunswick, New Jersey | United States | |
| Complete Women's Healthcare | Garden City, New York | United States | |
| North Shore University Hospital | Manhasset, New York | United States | |
| Madonna Perinatal | Mineola, New York | United States | |
| Long Island Jewish Medical Center | New Hyde Park, New York | United States | |
| New York University | New York, New York | United States | |
| Icahn School of Medicine Mt Sinai | New York, New York | United States | |
| Columbia University | New York, New York | United States | |
| Montefiore Medical Center | New York, New York | United States | |
| Suffolk OB | Port Jefferson, New York | United States | |
| North Austin Maternal Fetal Medicine | Austin, Texas | United States | |
| Zeid Women's Health Center | Longview, Texas | United States | |
| University of Utah | Salt Lake City, Utah | United States | |
| Royal Prince Alfred | Camperdown, New South Wales | Australia | |
| Royal College Surgeons in Ireland | Dublin | Ireland | |
| Dexeus | Barcelona | Spain | |
| Sahlgrenska University Hospital | Gothenburg | Sweden | |
| St. George University Hospital | London | United Kingdom | |
+Publications
- American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 581: the use of chromosomal microarray analysis in prenatal diagnosis. Obstet Gynecol. 2013 Dec;122(6):1374-7. doi: 10.1097/01.AOG.0000438962.16108.d1. PMID 24264715
- Results publication: Pergament E, Cuckle H, Zimmermann B, Banjevic M, Sigurjonsson S, Ryan A, Hall MP, Dodd M, Lacroute P, Stosic M, Chopra N, Hunkapiller N, Prosen DE, McAdoo S, Demko Z, Siddiqui A, Hill M, Rabinowitz M. Single-nucleotide polymorphism-based noninvasive prenatal screening in a high-risk and low-risk cohort. Obstet Gynecol. 2014 Aug;124(2 Pt 1):210-218. doi: 10.1097/AOG.0000000000000363. PMID 25004354
- Results publication: Ehrich M, Deciu C, Zwiefelhofer T, Tynan JA, Cagasan L, Tim R, Lu V, McCullough R, McCarthy E, Nygren AO, Dean J, Tang L, Hutchison D, Lu T, Wang H, Angkachatchai V, Oeth P, Cantor CR, Bombard A, van den Boom D. Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. Am J Obstet Gynecol. 2011 Mar;204(3):205.e1-11. doi: 10.1016/j.ajog.2010.12.060. Epub 2011 Feb 18. PMID 21310373
- Results publication: Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, Ehrich M, van den Boom D, Bombard AT, Deciu C, Grody WW, Nelson SF, Canick JA. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med. 2011 Nov;13(11):913-20. doi: 10.1097/GIM.0b013e3182368a0e. PMID 22005709
- Results publication: Sehnert AJ, Rhees B, Comstock D, de Feo E, Heilek G, Burke J, Rava RP. Optimal detection of fetal chromosomal abnormalities by massively parallel DNA sequencing of cell-free fetal DNA from maternal blood. Clin Chem. 2011 Jul;57(7):1042-9. doi: 10.1373/clinchem.2011.165910. Epub 2011 Apr 25. PMID 21519036
- Results publication: Benn P, Cuckle H, Pergament E. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet Gynecol. 2012 Jun;119(6):1270; author reply 1270-1. doi: 10.1097/AOG.0b013e318258c401. No abstract available. PMID 22617594
- Results publication: Palomaki GE, Deciu C, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, Ehrich M, van den Boom D, Bombard AT, Grody WW, Nelson SF, Canick JA. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study. Genet Med. 2012 Mar;14(3):296-305. doi: 10.1038/gim.2011.73. Epub 2012 Feb 2. PMID 22281937
- Results publication: Sparks AB, Struble CA, Wang ET, Song K, Oliphant A. Noninvasive prenatal detection and selective analysis of cell-free DNA obtained from maternal blood: evaluation for trisomy 21 and trisomy 18. Am J Obstet Gynecol. 2012 Apr;206(4):319.e1-9. doi: 10.1016/j.ajog.2012.01.030. Epub 2012 Jan 26. PMID 22464072
- Results publication: Norton ME, Brar H, Weiss J, Karimi A, Laurent LC, Caughey AB, Rodriguez MH, Williams J 3rd, Mitchell ME, Adair CD, Lee H, Jacobsson B, Tomlinson MW, Oepkes D, Hollemon D, Sparks AB, Oliphant A, Song K. Non-Invasive Chromosomal Evaluation (NICE) Study: results of a multicenter prospective cohort study for detection of fetal trisomy 21 and trisomy 18. Am J Obstet Gynecol. 2012 Aug;207(2):137.e1-8. doi: 10.1016/j.ajog.2012.05.021. Epub 2012 Jun 1. PMID 22742782
- Results publication: Nicolaides KH, Syngelaki A, Gil M, Atanasova V, Markova D. Validation of targeted sequencing of single-nucleotide polymorphisms for non-invasive prenatal detection of aneuploidy of chromosomes 13, 18, 21, X, and Y. Prenat Diagn. 2013 Jun;33(6):575-9. doi: 10.1002/pd.4103. Epub 2013 Apr 24. PMID 23613152
- Results publication: Nicolaides KH, Syngelaki A, del Mar Gil M, Quezada MS, Zinevich Y. Prenatal detection of fetal triploidy from cell-free DNA testing in maternal blood. Fetal Diagn Ther. 2014;35(3):212-7. doi: 10.1159/000355655. Epub 2013 Oct 10. PMID 24135152
- Results publication: Samango-Sprouse C, Banjevic M, Ryan A, Sigurjonsson S, Zimmermann B, Hill M, Hall MP, Westemeyer M, Saucier J, Demko Z, Rabinowitz M. SNP-based non-invasive prenatal testing detects sex chromosome aneuploidies with high accuracy. Prenat Diagn. 2013 Jul;33(7):643-9. doi: 10.1002/pd.4159. Epub 2013 Jun 20. PMID 23712453
- Results publication: Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, Savage M, Platt LD, Saltzman D, Grobman WA, Klugman S, Scholl T, Simpson JL, McCall K, Aggarwal VS, Bunke B, Nahum O, Patel A, Lamb AN, Thom EA, Beaudet AL, Ledbetter DH, Shaffer LG, Jackson L. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012 Dec 6;367(23):2175-84. doi: 10.1056/NEJMoa1203382. PMID 23215555
- Results publication: Wapner RJ, Babiarz JE, Levy B, Stosic M, Zimmermann B, Sigurjonsson S, Wayham N, Ryan A, Banjevic M, Lacroute P, Hu J, Hall MP, Demko Z, Siddiqui A, Rabinowitz M, Gross SJ, Hill M, Benn P. Expanding the scope of noninvasive prenatal testing: detection of fetal microdeletion syndromes. Am J Obstet Gynecol. 2015 Mar;212(3):332.e1-9. doi: 10.1016/j.ajog.2014.11.041. Epub 2014 Dec 2. PMID 25479548
- Results publication: Vora NL, O'Brien BM. Noninvasive prenatal testing for microdeletion syndromes and expanded trisomies: proceed with caution. Obstet Gynecol. 2014 May;123(5):1097-1099. doi: 10.1097/AOG.0000000000000237. PMID 24785862
- Results publication: Taglauer ES, Wilkins-Haug L, Bianchi DW. Review: cell-free fetal DNA in the maternal circulation as an indication of placental health and disease. Placenta. 2014 Feb;35 Suppl(Suppl):S64-8. doi: 10.1016/j.placenta.2013.11.014. Epub 2013 Dec 1. PMID 24388429
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- Results publication: Norton ME, MacPherson C, Demko Z, Egbert M, Malone F, Wapner RJ, Roman AS, Khalil A, Faro R, Madankumar R, Strong N, Haeri S, Silver R, Vohra N, Hyett J, Martin K, Rabinowitz M, Jacobsson B, Dar P. Obstetrical, perinatal, and genetic outcomes associated with nonreportable prenatal cell-free DNA screening results. Am J Obstet Gynecol. 2023 Sep;229(3):300.e1-300.e9. doi: 10.1016/j.ajog.2023.03.026. Epub 2023 Mar 23. PMID 36965866
- Results publication: Dar P, Jacobsson B, MacPherson C, Egbert M, Malone F, Wapner RJ, Roman AS, Khalil A, Faro R, Madankumar R, Edwards L, Haeri S, Silver R, Vohra N, Hyett J, Clunie G, Demko Z, Martin K, Rabinowitz M, Flood K, Carlsson Y, Doulaveris G, Malone C, Hallingstrom M, Klugman S, Clifton R, Kao C, Hakonarson H, Norton ME. Cell-free DNA screening for trisomies 21, 18, and 13 in pregnancies at low and high risk for aneuploidy with genetic confirmation. Am J Obstet Gynecol. 2022 Aug;227(2):259.e1-259.e14. doi: 10.1016/j.ajog.2022.01.019. Epub 2022 Jan 25. PMID 35085538
- Results publication: Dar P, Jacobsson B, Clifton R, Egbert M, Malone F, Wapner RJ, Roman AS, Khalil A, Faro R, Madankumar R, Edwards L, Strong N, Haeri S, Silver R, Vohra N, Hyett J, Demko Z, Martin K, Rabinowitz M, Flood K, Carlsson Y, Doulaveris G, Daly S, Hallingstrom M, MacPherson C, Kao C, Hakonarson H, Norton ME. Cell-free DNA screening for prenatal detection of 22q11.2 deletion syndrome. Am J Obstet Gynecol. 2022 Jul;227(1):79.e1-79.e11. doi: 10.1016/j.ajog.2022.01.002. Epub 2022 Jan 13. PMID 35033576
+Investigators
- Peer Dar, MD, Principal investigator, Montefiore Medical Center
- Mary Norton, MD, Principal investigator, University of California, San Francisco