SNP-based Microdeletion and Aneuploidy RegisTry (SMART) (SMART)

• Sponsor: Natera, Inc.
• Collaborators: George Washington University; University of California, San Francisco; Montefiore Medical Center; Children's Hospital of Philadelphia
• Information provided by (Responsible Party): Natera, Inc.

Study Description

Brief 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.

Condition or disease
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

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).

Study Design

Layout table for study information

Study Type :	Observational [Patient Registry]
Actual Enrollment :	20960 participants
Observational Model:	Cohort
Time Perspective:	Prospective
Target Follow-Up Duration:	2 Years
Official Title:	SNP-based Microdeletion and Aneuploidy RegisTry
Study Start Date :	April 2015
Estimated Primary Completion Date :	August 2019
Estimated Study Completion Date :	March 2020

Groups and Cohorts

Group/Cohort
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 Outcome Measures :

1. 22q11.2 Snp-based non-invasive prenatal screening test performance, including positive predictive value (PPV), specificity, and sensitivity [ Time Frame: 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 Outcome Measures :

1. Combined microdeletion syndrome screening test performance [ Time Frame: 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.
2. No call rate [ Time Frame: 3 years ]
   Determine the failure ('no call') rate for the NATUS method for 22q11.2 detection, as well as for aneuploidy.
3. Low fetal fraction aneuploidy risk refinement [ Time Frame: 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).
4. Placental mosaicism exploration [ Time Frame: 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.
5. Placental complications exploration [ Time Frame: 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).

Biospecimen Retention:   Samples With DNA

• Maternal residual blood sample
• Placental tissue
• Child dried blood spot
• Child buccal sample

Eligibility Criteria

Layout table for eligibility information

Ages Eligible for Study:	18 Years to 48 Years (Adult)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	Yes
Sampling Method:	Non-Probability Sample

Study Population

Pregnant women

Criteria

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

Contacts and Locations

Locations

Layout table for location information

United States, California
University of California, San Francisco
San Francisco, California, United States, 94158
United States, New Jersey
Cooper University Hospital
Camden, New Jersey, United States, 08103
Virtua
Mount Laurel, New Jersey, United States, 08054
St. Peter's University
New Brunswick, New Jersey, United States, 08901
United States, New York
Complete Women's Healthcare
Garden City, New York, United States, 11530
North Shore University Hospital
Manhasset, New York, United States, 11030
Madonna Perinatal
Mineola, New York, United States, 11501
Long Island Jewish Medical Center
New Hyde Park, New York, United States, 11040
New York University
New York, New York, United States, 10016
Icahn School of Medicine Mt Sinai
New York, New York, United States, 10029
Columbia University
New York, New York, United States, 10032
Montefiore Medical Center
New York, New York, United States, 10461
Suffolk OB
Port Jefferson, New York, United States, 11777
United States, Texas
North Austin Maternal Fetal Medicine
Austin, Texas, United States, 78758
Zeid Women's Health Center
Longview, Texas, United States, 75601
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84132
Australia, New South Wales
Royal Prince Alfred
Camperdown, New South Wales, Australia, 2050
Ireland
Royal College Surgeons in Ireland
Dublin, Ireland, 1
Spain
Dexeus
Barcelona, Spain, 08028
Sweden
Sahlgrenska University Hospital
Gothenburg, Sweden, SE-416 85
United Kingdom
St. George University Hospital
London, United Kingdom, SW17 0QT

Sponsors and Collaborators

Natera, Inc.

George Washington University

University of California, San Francisco

Montefiore Medical Center

Children's Hospital of Philadelphia

Investigators

Layout table for investigator information

Principal Investigator:	Peer Dar, MD	Montefiore Medical Center
Principal Investigator:	Mary Norton, MD	University of California, San Francisco

More Information

Additional Information:

1p36 Deletion Syndrome  Angelman Syndrome  Cri-du-chat Syndrome 

Publications of Results:

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):210-8. doi: 10.1097/AOG.0000000000000363.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Vora NL, OʼBrien BM. Noninvasive prenatal testing for microdeletion syndromes and expanded trisomies: proceed with caution. Obstet Gynecol. 2014 May;123(5):1097-9. doi: 10.1097/AOG.0000000000000237.

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:S64-8. doi: 10.1016/j.placenta.2013.11.014. Epub 2013 Dec 1. Review.

Knight M, Redman CW, Linton EA, Sargent IL. Shedding of syncytiotrophoblast microvilli into the maternal circulation in pre-eclamptic pregnancies. Br J Obstet Gynaecol. 1998 Jun;105(6):632-40.

Dar P, Curnow KJ, Gross SJ, Hall MP, Stosic M, Demko Z, Zimmermann B, Hill M, Sigurjonsson S, Ryan A, Banjevic M, Kolacki PL, Koch SW, Strom CM, Rabinowitz M, Benn P. Clinical experience and follow-up with large scale single-nucleotide polymorphism-based noninvasive prenatal aneuploidy testing. Am J Obstet Gynecol. 2014 Nov;211(5):527.e1-527.e17. doi: 10.1016/j.ajog.2014.08.006. Epub 2014 Aug 8.

Amos-Landgraf JM, Ji Y, Gottlieb W, Depinet T, Wandstrat AE, Cassidy SB, Driscoll DJ, Rogan PK, Schwartz S, Nicholls RD. Chromosome breakage in the Prader-Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints. Am J Hum Genet. 1999 Aug;65(2):370-86.

Roberts JM, Myatt L, Spong CY, Thom EA, Hauth JC, Leveno KJ, Pearson GD, Wapner RJ, Varner MW, Thorp JM Jr, Mercer BM, Peaceman AM, Ramin SM, Carpenter MW, Samuels P, Sciscione A, Harper M, Smith WJ, Saade G, Sorokin Y, Anderson GB; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Vitamins C and E to prevent complications of pregnancy-associated hypertension. N Engl J Med. 2010 Apr 8;362(14):1282-91. doi: 10.1056/NEJMoa0908056.

Tranquilli AL, Emanuelli M. The thrombophilic fetus. Med Hypotheses. 2006;67(5):1226-9. Epub 2006 Jul 11.

Faiz AS, Ananth CV. Etiology and risk factors for placenta previa: an overview and meta-analysis of observational studies. J Matern Fetal Neonatal Med. 2003 Mar;13(3):175-90.

Other 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.

Layout table for additonal information

Responsible Party:	Natera, Inc.
ClinicalTrials.gov Identifier:	NCT02381457 History of Changes
Other Study ID Numbers:	14-024-NPT
First Posted:	March 6, 2015
Last Update Posted:	February 7, 2019
Last Verified:	February 2019

Keywords provided by Natera, Inc.:

Microdeletion Syndrome; Aneuploidy; 22q; Non-Invasive Prenatal Screening; DiGeorge Syndrome

Additional relevant MeSH terms:

Layout table for MeSH terms

Syndrome; Prader-Willi Syndrome; Aneuploidy; Trisomy; Down Syndrome; Angelman Syndrome; DiGeorge Syndrome; Craniosynostoses; Marfan Syndrome; Arachnodactyly; Chromosome Aberrations; Chromosome Disorders; Monosomy; Trisomy 13 Syndrome; Trisomy 18 Syndrome	Sex Chromosome Aberrations; 22q11 Deletion Syndrome; Chromosome Deletion; Cri-du-Chat Syndrome; Disease; Pathologic Processes; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Abnormalities, Multiple; Congenital Abnormalities; Genetic Diseases, Inborn; Obesity; Overnutrition