SNP-based Microdeletion and Aneuploidy RegisTry (SMART)

Overview

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.

Full Title of Study: “SNP-based Microdeletion and Aneuploidy RegisTry”

Study Type

  • Study Type: Observational [Patient Registry]
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: April 2020

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, Groups and Cohorts

  • 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.

Clinical Trial Outcome Measures

Primary Measures

  • 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 Measures

  • 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.
  • 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.
  • 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).
  • 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.
  • 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).

Participating in This Clinical Trial

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

Gender Eligibility: Female

Minimum Age: 18 Years

Maximum Age: 48 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Natera, Inc.
  • Collaborator
    • George Washington University
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Peer Dar, MD, Principal Investigator, Montefiore Medical Center
    • Mary Norton, MD, Principal Investigator, University of California, San Francisco

References

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.

Citations Reporting on Results

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