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

SNP-based Microdeletion and Aneuploidy RegisTry

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.

Study Overview

• Status: Completed
• Conditions: Prader-Willi Syndrome; DiGeorge Syndrome; 22q11 Deletion Syndrome; Angelman Syndrome; Trisomy 21; Trisomy 18; Trisomy 13; Monosomy X; Sex Chromosome Abnormalities; 1p36 Deletion Syndrome; Cri-du-Chat 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 Type: Observational
• Enrollment (Actual): 20960

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 44 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Pregnant women

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
22q11.2 Snp-based non-invasive prenatal screening test performance, including positive predictive value (PPV), specificity, and sensitivity	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.	3 years

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Natera, Inc.
• Collaborators: Children's Hospital of Philadelphia; Montefiore Medical Center; University of California, San Francisco; George Washington University
• Investigators: Principal Investigator: Mary Norton, MD, University of California, San Francisco; Principal Investigator: Peer Dar, MD, Montefiore Medical Center

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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. No abstract available.
• 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, 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.
• 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.
• 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. doi: 10.1111/j.1471-0528.1998.tb10178.x.
• 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. doi: 10.1086/302510.
• 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. doi: 10.1016/j.mehy.2006.04.046. 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. doi: 10.1080/jmf.13.3.175.190.
• 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.
• 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.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2015
• Primary Completion (Actual): June 1, 2020
• Study Completion (Actual): June 1, 2020

Study Registration Dates

• First Submitted: March 2, 2015
• First Submitted That Met QC Criteria: March 2, 2015
• First Posted (Estimate): March 6, 2015

Study Record Updates

• Last Update Posted (Actual): January 29, 2021
• Last Update Submitted That Met QC Criteria: January 27, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Aneuploidy; 22q; DiGeorge Syndrome; Microdeletion Syndrome; Non-Invasive Prenatal Screening
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Central Nervous System Diseases; Nervous System Diseases; Lymphatic Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Endocrine System Diseases; Disease; Congenital Abnormalities; Overnutrition; Nutrition Disorders; Genetic Diseases, Inborn; Musculoskeletal Diseases; Parathyroid Diseases; Movement Disorders; Intellectual Disability; Heart Defects, Congenital; Cardiovascular Abnormalities; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Abnormalities, Multiple; Obesity; Chromosome Duplication; Lymphatic Abnormalities; Hypoparathyroidism; Syndrome; Down Syndrome; Prader-Willi Syndrome; Aneuploidy; Chromosome Disorders; Chromosome Aberrations; Angelman Syndrome; Trisomy; Trisomy 13 Syndrome; Trisomy 18 Syndrome; Monosomy; Sex Chromosome Aberrations; DiGeorge Syndrome; 22q11 Deletion Syndrome; Cri-du-Chat Syndrome
• Other Study ID Numbers: 14-024-NPT