Prenatal Genetic Diagnosis by Genomic Sequencing: A Prospective Evaluation
Overview
- Phase
- Not Applicable
- Intervention
- Not specified
- Conditions
- Fetal Structural Anomalies
- Sponsor
- Columbia University
- Enrollment
- 1097
- Locations
- 5
- Primary Endpoint
- Number of Participants Who Had Reportable Variants
- Status
- Completed
- Last Updated
- 6 months ago
Overview
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.
Investigators
Ronald J Wapner, MD
Director, Reproductive Genetics, Department of OBGYN
Columbia University
Eligibility Criteria
Inclusion Criteria
- •Prenatal sequencing group
- •Fetus identified by ultrasound and/or MRI with at least one of the following:
- •One or more major structural anomalies (Appendix A)
- •A nuchal translucency measurement of ≥ 3.5 mm
- •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.
- •Negative prenatal CMA (or those with CMA findings not related to the ultrasound finding)
- •Singleton or twin gestation
- •Gestational age less than 36 weeks, 0 days to allow for availability of sequencing results before delivery
- •Unsequenced Group
- •Fetus identified by ultrasound and/or MRI with at least one of the following:
Exclusion Criteria
- •Prenatal Sequencing Group
- •Prenatal sequencing or planned prenatal sequencing performed outside of the study, including gene panels
- •Maternal or paternal age less than 18 years old
- •Proven infectious or teratogenic cause of fetal anomaly
- •Planned termination of the pregnancy
- •Unavailable blood or saliva samples from both biologic parents prior to sequencing
- •Parental unwillingness to participate in 1 year postnatal follow-up
- •Language barrier (non-English or Spanish speaking)
- •Previous consent to the unsequenced prenatal group or enrollment in a previous pregnancy
- •Unsequenced Group
Outcomes
Primary Outcomes
Number of Participants Who Had Reportable Variants
Time Frame: At end of study, approx 4 years
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.
Healthcare Costs
Time Frame: From time of diagnosis of anomaly to infant discharge
Healthcare costs from time of diagnosis of anomaly to infant discharge between sequenced and unsequenced groups.
Secondary Outcomes
- Gestational Age at Delivery(At time of delivery)
- Neonatal Outcomes(Up to 28 days after birth)
- Number of Deaths(From discharge to 12 months postpartum)
- NICU Stay Duration(From discharge to 12 months postpartum)
- Length in Centimeters(12 months postpartum)
- Weight in Kilograms(12 months postpartum)
- Score on Development by Ages and Stages Questionnaire (ASQ-3)(12 months postpartum)
- Anxiety by Self-report Questionnaire(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(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(Approximately 4.5 years)
- QALY, Measured in Cost Per Year(Approximately 4.5 years)
- Total Number of Identified Phenotypes Associated With Disease- Sequenced Group ONLY(12 months postpartum)
- Number of Participants With VUS - Sequenced Group ONLY(12 months postpartum)
- Number of Participants With Variants Classified as GUS - Sequenced Group ONLY(12 months postpartum)
- Digital WES - Comparison of Coding and Non-coding Results - Sequenced Group ONLY(Approximately 4.5 years)
- Change in Management (Healthcare) as Determined by NICU Physician and Record Review - Sequenced Group ONLY(From delivery until discharge or death (neonatal))
- Turnaround Time - Sequenced Group ONLY(Time from sequencing initiation until study site result, up to 38 days)
- Proband Only Versus Trio - Comparison of Results Between Trio and Proband Only - Sequenced Group ONLY(Approximately 4.5 years)
- Parental Support Needs by Self-report Questionnaire - Sequenced Group ONLY(At sequencing completion, approximately 4.5 years)
- Parental Understanding by Self-report Questionnaire - Sequenced Group ONLY(At sequencing completion, approximately 4.5 years)
- Number of Participants Who Had a Change in the Sequencing Result - Sequenced Group ONLY(From sequencing completion to data analysis period, up to 4.5 years)