Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Prenatal Genetic Diagnosis by Genomic Sequencing (PrenatalSEQ)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03936101
Recruitment Status : Recruiting
First Posted : May 3, 2019
Last Update Posted : August 24, 2020
Sponsor:
Collaborators:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Baylor College of Medicine
University of North Carolina
The George Washington University Biostatistics Center
Oregon Health and Science University
Information provided by (Responsible Party):
Ronald J Wapner, MD, Columbia University

Brief Summary:
This study is evaluating the impact of prenatal sequencing on the management of fetuses with ultrasound abnormalities. The hypothesis is that a significant subset of fetal abnormalities have a genetic cause that can be identified by sequencing and that prenatal knowledge of this information will improve prenatal care, reduce unnecessary diagnostic testing, reduce the cost of care, and improve the quality of life for both the child and the family.

Condition or disease Intervention/treatment
Fetal Structural Anomalies Diagnostic Test: Prenatal Genomic Sequencing

Detailed Description:

Whole exome and whole genome sequencing (WGS) have expanded the ability to determine the genetic etiology of previously undiagnosed disorders. This study is a multicenter prospective cohort study to evaluate the emerging technology of sequencing for the management of fetuses with structural anomalies. The hypothesis is that a significant subset of fetal structural anomalies has a genetic etiology identifiable by sequencing and that prenatal knowledge of this information will improve perinatal care, reduce unnecessary diagnostic testing, reduce the cost of care, and improve quality of life for both the child and the family. The aims of this study are to investigate these multiple aspects of prenatal sequencing in a single study with an innovative integrated prospective design, which will permit a robust evaluation of the benefits and risks of delivering diagnostic and prognostic genetic testing results in a prenatal setting.

The study will determine, in a sequential population of pregnancies with selected fetal structural anomalies and a negative or non-causal chromosomal microarray (CMA), the frequency of pathogenic, likely pathogenic, and uncertain genomic variants identifiable by sequencing. To determine the impact of this information on clinical care, a control population of unsequenced pregnancies with similar structural anomalies will be prospectively recruited and the infants from both cohorts will be followed up to 1 year of age. This study component will evaluate differences in healthcare management and cost through discharge from hospital post-delivery, and perinatal and infant outcomes through 1 year of life. The educational, counseling and psychosocial impact of sequencing results during the prenatal period, in the nursery and through 1 year of life also will be evaluated. Since the analytical and clinical tools needed for the full translation of sequencing into care are still developing, optimization of bioinformatic tools to improve identification of pathogenic and likely pathogenic mutations associated with prenatal phenotypes of established disease genes will be investigated, as well as identification of new genes associated with presently undiagnosed fetal/neonatal phenotypes. This study will provide an in-depth evaluation of the prenatal diagnostic value of sequencing prior to its responsible introduction into practice and will provide independent data to guide its translation.

Layout table for study information
Study Type : Observational
Estimated Enrollment : 1100 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Prenatal Genetic Diagnosis by Genomic Sequencing: A Prospective Evaluation
Actual Study Start Date : June 28, 2019
Estimated Primary Completion Date : August 31, 2023
Estimated Study Completion Date : November 30, 2023

Group/Cohort Intervention/treatment
Prenatally Sequenced Group
750 trios with fetal structural anomalies who receive prenatal sequencing from the study
Diagnostic Test: Prenatal Genomic Sequencing
Whole genome sequencing (which initially will be masked and reported as exome only)

No Prenatal Sequencing (Unsequenced) Group
350 trios with fetal structural anomalies who do not have prenatal sequencing



Primary Outcome Measures :
  1. Reportable Variants [ Time Frame: Approximately 4.5 years ]
    Reportable variants (defined as either Pathogenic, likely pathogenic, or VUS) identified by sequencing and deemed reportable by the Variant Adjudication Committee.

  2. Healthcare Costs [ Time Frame: Approximately 4.5 years ]
    Healthcare costs from time of diagnosis of anomaly to infant discharge between sequenced and unsequenced groups.


Secondary Outcome Measures :
  1. Perinatal Outcomes by Medical Record Review [ Time Frame: Approximately 4.5 years ]
    Perinatal outcomes will be compared and outcomes will be measured by: gestational age at delivery, major morbidities including length of ventilator support, sepsis, need for pressor support, need for ECMO, metabolic abnormalities (e.g., acidosis, elevated uric acid, hypo-/hyperglycemia), intraventricular hemorrhage/periventricular leukomalacia, encephalopathy, and seizure.

  2. Death [ Time Frame: Approximately 4.5 years ]
    Neonatal/infant death at time of discharge and at 12 months of age.

  3. NICU Stay Duration [ Time Frame: Approximately 4.5 years ]
    Length of initial NICU stay and number of days spent in the hospital between initial discharge and 12 months of age.

  4. Length in centimeters [ Time Frame: Approximately 4.5 years ]
    Infant length at 12 months of age.

  5. Weight in kilograms [ Time Frame: Approximately 4.5 years ]
    Infant weight at 12 months of age.

  6. Development by Ages and Stages Questionnaire [ Time Frame: Approximately 4.5 years ]
    Developmental outcomes defined by the following parameters: communication, gross motor, fine motor, problem solving and personal-social, at 12 months of age using ASQ-3. Lower scores are associated with developmental delay. Cutoffs for 12 month exam are: Communication 15.64, Gross Motor 21.49, Fine Motor 34.5, Problem Solving 27.32, Personal-Social 21.73

  7. Anxiety by self-report questionnaire [ Time Frame: Approximately 4.5 years ]
    Anxiety following result disclosure (or 8 weeks post enrollment for the unsequenced group), neonatal discharge and 12 months postpartum.

  8. Depression/Anxiety by self-report questionnaire [ Time Frame: Approximately 4.5 years ]
    Depression following result disclosure (or 8 weeks post enrollment for the unsequenced group), neonatal discharge and 12 months postpartum.

  9. Quality of Life by self-report questionnaire [ Time Frame: Approximately 4.5 years ]
    Quality of life for the patient and family at 12 months postpartum.

  10. QALY, measured in cost per year [ Time Frame: Approximately 4.5 years ]
    Incremental cost per Quality Adjusted Life Year (QALY).

  11. Phenotypic Expansion - identification of new phenotypes associated with disease- Sequenced Group ONLY [ Time Frame: Approximately 4.5 years ]
    Apparent prenatal phenotypic expansion from currently defined pediatric phenotypes.

  12. VUS frequency and outcome- Sequenced Group ONLY [ Time Frame: Approximately 4.5 years ]
    Variants of uncertain significance (VUS) that have not yet been associated with this disease phenotype.

  13. GUS frequency and outcome- Sequenced Group ONLY [ Time Frame: Approximately 4.5 years ]
    VUS subclassified as compelling variants in novel genes that are not yet disease associated (genes of uncertain clinical significance; GUS).

  14. Digital WES - comparison of coding and non-coding results - Sequenced Group ONLY [ Time Frame: Approximately 4.5 years ]
    Pathogenic, likely pathogenic and VUS variants identified by sequencing (coding and non-coding regions) compared with coding regions only (digital WES).

  15. Proband Only Versus Trio - comparison of results between trio and proband only - Sequenced Group ONLY [ Time Frame: Approximately 4.5 years ]
    Pathogenic, likely pathogenic and VUS variants identified by analysis of a proband alone compared to a proband-parent trio.

  16. Change in Management (healthcare) as Determined by NICU physician and record review - Sequenced Group ONLY [ Time Frame: Approximately 4.5 years ]
    Change in management decisions attributable to genomic results defined as changes to the patient's treatment plan or changes to the counseling of the patient/family regarding the immediate or long-term medical management.

  17. Parental Understanding by self-report questionnaire - Sequenced Group ONLY [ Time Frame: Approximately 4.5 years ]
    Accuracy of parental understanding of genetic test results.

  18. Parental Support Needs - by self-report questionnaire - Sequenced Group ONLY [ Time Frame: Approximately 4.5 years ]
    Educational/counseling and social support needs of the mother and father.

  19. Classification Over Time (Change in the sequencing result over time) - Sequenced Group ONLY [ Time Frame: Approximately 4.5 years ]
    Changes in classification of sequencing variants over time.

  20. Turnaround Time - Sequenced Group ONLY [ Time Frame: Approximately 4.5 years ]
    Turnaround time of sequencing components and how it changes over time.


Biospecimen Retention:   Samples With DNA
Remaining DNA from trios will be stored in a biorepository. Plasma from Streck tubes will be retained as well.


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

A total of 1,100 pregnancies with fetal structural anomalies and meeting eligibility criteria will be enrolled into the study. Of these, 750 will undergo prenatal genomic sequencing (prenatal sequencing group) and the remaining 350 pregnancies will not have any prenatal genomic sequencing (unsequenced prenatal group).

Enrollment of pregnancies with an isolated nuchal translucency measurements ≥ 3.5 mm will be restricted to 5% within each group (sequenced and unsequenced) and isolated estimated fetal weight <5th %ile also will be restricted to 5% for each group (sequenced and unsequenced).

Criteria

Inclusion Criteria:

Prenatal sequencing group

  1. Fetus identified by ultrasound and/or MRI with at least one of the following:

    1. One or more major structural anomalies (Appendix A)
    2. A nuchal translucency measurement of ≥ 3.5 mm
    3. A fetus less than 24 weeks 0 days gestation with normal anatomy and sonographically estimated fetal weight <5th %ile without maternal hypertension, type I diabetes, or other maternal disorders known to alter fetal growth.
  2. Negative prenatal CMA (or those with CMA findings not related to the ultrasound finding)
  3. Singleton gestation
  4. Gestational age less than 36 weeks, 0 days to allow for availability of sequencing results before delivery

Unsequenced Group

  1. Fetus identified by ultrasound and/or MRI with at least one of the following:

    1. One or more major structural anomalies (Appendix A)
    2. A nuchal translucency measurement of ≥ 3.5 mm
    3. A fetus less than 24 weeks 0 days gestation with normal anatomy and sonographically estimated fetal weight <5th %ile without maternal hypertension, type I diabetes, or other maternal disorders known to alter fetal growth
  2. Negative prenatal or postnatal CMA (or those with CMA findings not related to the ultrasound finding)
  3. Declined prenatal sequencing
  4. Singleton gestation

Exclusion Criteria:

Prenatal Sequencing Group

  1. Prenatal sequencing or planned prenatal sequencing performed outside of the study, including gene panels
  2. Maternal or paternal age less than 18 years old
  3. Proven infectious or teratogenic cause of fetal anomaly
  4. Planned termination of the pregnancy
  5. Unavailable blood or saliva samples from both biologic parents prior to sequencing
  6. Parental unwillingness to participate in 1 year postnatal follow-up
  7. Language barrier (non-English or Spanish speaking)
  8. Delivery planned at a site other than one of the study centers or associated hospitals
  9. Previous consent to the unsequenced prenatal group or enrollment in a previous pregnancy

Unsequenced Group

  1. Maternal or paternal age less than 18 years old
  2. Proven infectious or teratogenic cause of fetal anomaly
  3. Positive prenatal NIPT screening for trisomy 21,18 or 13. Positive 22q11.2 prenatal NIPT testing with consistent ultrasound findings is also an exclusion.
  4. Planned termination of the pregnancy
  5. Parental unwillingness to participate in 1 year postnatal follow-up
  6. Language barrier (non-English or Spanish speaking)
  7. Delivery planned at a site other than one of the study centers or associated hospitals

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03936101


Contacts
Layout table for location contacts
Contact: Melissa Stosic, MS 646-565-9501 ms3342@cumc.columbia.edu

Locations
Layout table for location information
United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Ronald Wapner, MD    212-305-1521      
United States, North Carolina
University of North Carolina Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27514
Contact: Kelly Gilmore, MS    919-966-2229    Kelly_gilmore@med.unc.edu   
Principal Investigator: Neeta Vora, MD         
United States, Texas
Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030
Contact: Lauren Westerfield, MS, CGC    832-826-7483    lewester@texaschildrens.org   
Principal Investigator: Ignatia Van den Veyver, MD         
Sponsors and Collaborators
Columbia University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Baylor College of Medicine
University of North Carolina
The George Washington University Biostatistics Center
Oregon Health and Science University
Investigators
Layout table for investigator information
Principal Investigator: Ronald Wapner, MD Columbia University Irving Medical Center
Layout table for additonal information
Responsible Party: Ronald J Wapner, MD, Director, Reproductive Genetics, Vice Chair of Research, Department of OBGYN, Columbia University
ClinicalTrials.gov Identifier: NCT03936101    
Other Study ID Numbers: AAAS2118
First Posted: May 3, 2019    Key Record Dates
Last Update Posted: August 24, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: In accordance with the NIH Genomic Data Sharing policy, sequencing data (including VCF files) and clinical data will be shared with other scientific investigators and through the controlled access dbGAP repository or comparable genomics commons, the Sequence Read Archive, and any NIH Birth Defects Commons that is established. A final dataset containing clinical and phenotypic data will be submitted to the NICHD data repository (DASH). In addition, new algorithms and allele frequency data will be shared with the newly developed Precision FDA platform as applicable.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: After study completion.
Access Criteria: Through dbGaP or other controlled access databases.

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No