Prenatal Genetic Diagnosis by Genomic Sequencing (PrenatalSEQ)
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|ClinicalTrials.gov Identifier: NCT03936101|
Recruitment Status : Recruiting
First Posted : May 3, 2019
Last Update Posted : December 5, 2019
|Condition or disease||Intervention/treatment|
|Fetal Structural Anomalies||Diagnostic Test: Prenatal Genomic Sequencing|
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|
|Estimated Enrollment :||1100 participants|
|Official Title:||Prenatal Genetic Diagnosis by Genomic Sequencing: A Prospective Evaluation|
|Actual Study Start Date :||May 21, 2019|
|Estimated Primary Completion Date :||May 6, 2022|
|Estimated Study Completion Date :||August 31, 2023|
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
- 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.
- 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.
Biospecimen Retention: Samples With DNA
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03936101
|Contact: Melissa Stosic, MSfirstname.lastname@example.org|
|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 email@example.com|
|Principal Investigator: Ignatia Van den Veyver, MD|
|Principal Investigator:||Ronald Wapner, MD||Columbia University Irving Medical Center|