Prenatal Genetic Diagnosis by Genomic Sequencing (PrenatalSEQ)

Prenatal Genetic Diagnosis by Genomic Sequencing: A Prospective Evaluation

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.

Study Overview

• Status: Completed
• Conditions: Fetal Structural Anomalies
• Intervention / Treatment: 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.

• Study Type: Observational
• Enrollment (Actual): 1097

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina Chapel Hill
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Children's Hospital, Cincinnati Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Houston, Texas, United States, 77030
      • UT Health Houston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• 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).

Description

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)

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Had Reportable Variants	Reportable variants: defined as either Pathogenic / Likely pathogenic (P/LP) or variant of uncertain significance (VUS) identified by sequencing and deemed reportable by the Variant Adjudication Committee.	At end of study, approx 4 years
Healthcare Costs	Healthcare costs from time of diagnosis of anomaly to infant discharge between sequenced and unsequenced groups.	From time of diagnosis of anomaly to infant discharge

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gestational Age at Delivery	Gestational age of newborn at delivery (in weeks)	At time of delivery
Neonatal Outcomes	Neonatal outcomes will be compared and outcomes will be measured by the number of newborns who experience: need for ventilator support, sepsis, need for pressor support, need for extracorporeal membrane oxygenation (ECMO), metabolic abnormalities (e.g., acidosis, elevated uric acid, hypo-/hyperglycemia), intraventricular hemorrhage, periventricular leukomalacia, encephalopathy, and seizure.	Up to 28 days after birth
Number of Deaths	Neonatal/infant death at time of discharge and at 12 months of age.	From discharge to 12 months postpartum
NICU Stay Duration	Length of initial NICU stay and number of days spent in the hospital between initial discharge and 12 months of age.	From discharge to 12 months postpartum
Length in Centimeters	Infant length at 12 months of age.	12 months postpartum
Weight in Kilograms	Infant weight at 12 months of age.	12 months postpartum
Score on Development by Ages and Stages Questionnaire (ASQ-3)	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. For each developmental area, parents may answer YES=10, SOMETIMES=5, or NOT YET=0 by filling in a bubble for each item response. The full score range for each domain is 0 to 60. Cutoffs for each domain are: Communication 15.64, Gross Motor 21.49, Fine Motor 34.5, Problem Solving 27.32, Personal-Social 21.73	12 months postpartum
Anxiety by Self-report Questionnaire	Anxiety following result disclosure (or 8 weeks post enrollment for the unsequenced group), neonatal discharge and 12 months postpartum. The full score range is 0 to 21, where lower numbers represent lower anxiety (better outcome).	2 weeks after disclosure of study sequencing results or 4 weeks after enrollment for the unsequenced group; 1 month after discharge from the hospital or end of the pregnancy if there was a fetal demise or pregnancy termination; 12-15 months postpartum
Depression by Self-report Questionnaire	Depression following result disclosure (or 8 weeks post enrollment for the unsequenced group), neonatal discharge and 12 months postpartum. The full score range is 0 to 24, where a lower score represents lower depression (better outcome).	2 weeks after disclosure of study sequencing results or 4 weeks after enrollment for the unsequenced group; 1 month after discharge from the hospital or end of the pregnancy if there was a fetal demise or pregnancy termination; 12-15 months postpartum
Quality of Life by Self-report Questionnaire	Quality of life for the patient and family at 12 months postpartum.	Approximately 4.5 years
QALY, Measured in Cost Per Year	Incremental cost per Quality Adjusted Life Year (QALY).	Approximately 4.5 years
Total Number of Identified Phenotypes Associated With Disease- Sequenced Group ONLY	Phenotypic Expansion: Apparent prenatal phenotypic expansion from currently defined pediatric phenotypes.	12 months postpartum
Number of Participants With VUS - Sequenced Group ONLY	Variants of uncertain significance (VUS) that have not yet been associated with this disease phenotype. This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm.	12 months postpartum
Number of Participants With Variants Classified as GUS - Sequenced Group ONLY	VUS subclassified as compelling variants in novel genes that are not yet disease associated (genes of uncertain clinical significance; GUS). This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm.	12 months postpartum
Digital WES - Comparison of Coding and Non-coding Results - Sequenced Group ONLY	Pathogenic, likely pathogenic and VUS variants identified by sequencing (coding and non-coding regions) compared with coding regions only (digital WES).	Approximately 4.5 years
Proband Only Versus Trio - Comparison of Results Between Trio and Proband Only - Sequenced Group ONLY	Pathogenic, likely pathogenic and VUS variants identified by analysis of a proband alone compared to a proband-parent trio.	Approximately 4.5 years
Change in Management (Healthcare) as Determined by NICU Physician and Record Review - Sequenced Group ONLY	Number of participants who had a 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. This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm.	From delivery until discharge or death (neonatal)
Parental Support Needs by Self-report Questionnaire - Sequenced Group ONLY	Assessment of educational/counseling and social support needs of the mother and father. The full score range is 12 to 60, where a higher score represents a higher satisfaction with the experience (better outcome).	At sequencing completion, approximately 4.5 years
Parental Understanding by Self-report Questionnaire - Sequenced Group ONLY	Accuracy of parental understanding of genetic test results. The parental responses to the question "How well do you understand your prenatal genetic test results?" will be collected. All possible responses are: "Not at all", "A little bit", "Moderately", "Quite a bit", and "Extremely"	At sequencing completion, approximately 4.5 years
Number of Participants Who Had a Change in the Sequencing Result - Sequenced Group ONLY	Reinterpretations of sequencing results that lead to a change in classification of sequencing variants. This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm.	From sequencing completion to data analysis period, up to 4.5 years
Turnaround Time - Sequenced Group ONLY	Turnaround time of sequencing components and how it changes over time. This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm.	Time from sequencing initiation until study site result, up to 38 days

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); The University of Texas Health Science Center, Houston; Baylor College of Medicine; Oregon Health and Science University; Children's Hospital Medical Center, Cincinnati; University of North Carolina; The George Washington University Biostatistics Center; The Jackson Laboratory; Broad Institute of MIT and Harvard
• Investigators: Principal Investigator: Ronald Wapner, MD, Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): June 28, 2019
• Primary Completion (Actual): March 25, 2024
• Study Completion (Actual): March 25, 2024

Study Registration Dates

• First Submitted: March 25, 2019
• First Submitted That Met QC Criteria: April 30, 2019
• First Posted (Actual): May 3, 2019

Study Record Updates

• Last Update Posted (Estimated): October 27, 2025
• Last Update Submitted That Met QC Criteria: October 14, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Other Study ID Numbers: AAAS2118; R01HD055651 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.
• IPD Sharing Time Frame: After study completion.
• IPD Sharing Access Criteria: Through dbGaP or other controlled access databases.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No