Prenatal Genetic Diagnosis by Genomic Sequencing (PrenatalSEQ)

• ClinicalTrials.gov Identifier: NCT03936101
• Recruitment Status: Recruiting
• First Posted: May 3, 2019
• Last Update Posted: October 24, 2022
• Sponsor: Columbia University
• 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; Children's Hospital Medical Center, Cincinnati; The University of Texas Health Science Center, Houston; Broad Institute; The Jackson Laboratory
• Information provided by (Responsible Party): Ronald J Wapner, MD, Columbia University

Tracking Information

• First Submitted Date: March 25, 2019
• First Posted Date: May 3, 2019
• Last Update Posted Date: October 24, 2022
• Actual Study Start Date: June 28, 2019
• Estimated Primary Completion Date: August 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 30, 2019)

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 30, 2019)

• 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.
• Death [ Time Frame: Approximately 4.5 years ]
  Neonatal/infant death at time of discharge and at 12 months of age.
• 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.
• Length in centimeters [ Time Frame: Approximately 4.5 years ]
  Infant length at 12 months of age.
• Weight in kilograms [ Time Frame: Approximately 4.5 years ]
  Infant weight at 12 months of age.
• 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
• 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.
• 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.
• 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.
• QALY, measured in cost per year [ Time Frame: Approximately 4.5 years ]
  Incremental cost per Quality Adjusted Life Year (QALY).
• 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.
• 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.
• 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).
• 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).
• 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.
• 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.
• Parental Understanding by self-report questionnaire - Sequenced Group ONLY [ Time Frame: Approximately 4.5 years ]
  Accuracy of parental understanding of genetic test results.
• 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.
• 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.
• Turnaround Time - Sequenced Group ONLY [ Time Frame: Approximately 4.5 years ]
  Turnaround time of sequencing components and how it changes over time.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Prenatal Genetic Diagnosis by Genomic Sequencing
• Official Title: Prenatal Genetic Diagnosis by Genomic Sequencing: A Prospective Evaluation
• 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.

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.

• Study Type: Observational
• Study Design: Observational Model: Case-Control; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples With DNA

Description:

Remaining DNA from trios will be stored in a biorepository. Plasma from Streck tubes will be retained as well.

• 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).

• Condition: Fetal Structural Anomalies

Intervention

Diagnostic Test: Prenatal Genomic Sequencing

Whole genome sequencing (which initially will be masked and reported as exome only)

Study Groups/Cohorts

• Prenatally Sequenced Group
  750 trios with fetal structural anomalies who receive prenatal sequencing from the study
  Intervention: Diagnostic Test: Prenatal Genomic Sequencing
• No Prenatal Sequencing (Unsequenced) Group
  350 trios with fetal structural anomalies who do not have prenatal sequencing

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 30, 2019): 1100
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: November 2023
• Estimated Primary Completion Date: August 2023 (Final data collection date for primary outcome measure)

Eligibility 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 or twin 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. 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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Jessica L Giordano, CGC; 516-521-5604; jlg2197@cumc.columbia.edu

Contact: Ronnie J Loosen; 415-652-1177; rla2156@cumc.columbia.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03936101
• Other Study ID Numbers: AAAS2118; R01HD055651 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

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
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: After study completion.
• Access Criteria: Through dbGaP or other controlled access databases.

• Current Responsible Party: Ronald J Wapner, MD, Columbia University
• Original Responsible Party: Ronald J Wapner, MD, Columbia University, Director, Reproductive Genetics, Vice Chair of Research, Department of OBGYN
• Current Study Sponsor: Columbia University
• Original Study Sponsor: Same as current

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
• Children's Hospital Medical Center, Cincinnati
• The University of Texas Health Science Center, Houston
• Broad Institute
• The Jackson Laboratory

Investigators

• Principal Investigator: Ronald Wapner, MD; Columbia University

• PRS Account: Columbia University
• Verification Date: October 2022