Clinical trial NCT03936101: Prenatal Genetic Diagnosis by Genomic Sequencing
Official title: Prenatal Genetic Diagnosis by Genomic Sequencing: A Prospective Evaluation
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Fetal Structural Anomalies
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Baylor College of Medicine
name: University of North Carolina
name: The George Washington University Biostatistics Center
name: Oregon Health and Science University
name: Children's Hospital Medical Center, Cincinnati
name: The University of Texas Health Science Center, Houston
name: Broad Institute of MIT and Harvard
name: The Jackson Laboratory
First posted: 2019-05-03
Enrollment: 1097
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
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).

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.

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)

Primary outcomes:
measure: Reportable Variants
timeFrame: Approximately 4.5 years
measure: Healthcare Costs
timeFrame: Approximately 4.5 years
Secondary outcomes:
measure: Perinatal Outcomes by Medical Record Review
timeFrame: Approximately 4.5 years
measure: Death
timeFrame: Approximately 4.5 years
measure: NICU Stay Duration
timeFrame: Approximately 4.5 years
measure: Length in centimeters
timeFrame: Approximately 4.5 years
measure: Weight in kilograms
timeFrame: Approximately 4.5 years
measure: Development by Ages and Stages Questionnaire
timeFrame: Approximately 4.5 years
measure: Anxiety by self-report questionnaire
timeFrame: Approximately 4.5 years
measure: Depression/Anxiety by self-report questionnaire
timeFrame: Approximately 4.5 years
measure: Quality of Life by self-report questionnaire
timeFrame: Approximately 4.5 years
measure: QALY, measured in cost per year
timeFrame: Approximately 4.5 years
measure: Phenotypic Expansion - identification of new phenotypes associated with disease- Sequenced Group ONLY
timeFrame: Approximately 4.5 years
measure: VUS frequency and outcome- Sequenced Group ONLY
timeFrame: Approximately 4.5 years
measure: GUS frequency and outcome- Sequenced Group ONLY
timeFrame: Approximately 4.5 years
measure: Digital WES - comparison of coding and non-coding results - Sequenced Group ONLY
timeFrame: Approximately 4.5 years
measure: Proband Only Versus Trio - comparison of results between trio and proband only - Sequenced Group ONLY
timeFrame: Approximately 4.5 years
measure: Change in Management (healthcare) as Determined by NICU physician and record review - Sequenced Group ONLY
timeFrame: Approximately 4.5 years
measure: Parental Understanding by self-report questionnaire - Sequenced Group ONLY
timeFrame: Approximately 4.5 years
measure: Parental Support Needs - by self-report questionnaire - Sequenced Group ONLY
timeFrame: Approximately 4.5 years
measure: Classification Over Time (Change in the sequencing result over time) - Sequenced Group ONLY
timeFrame: Approximately 4.5 years
measure: Turnaround Time - Sequenced Group ONLY
timeFrame: Approximately 4.5 years
Other outcomes:
Locations:
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Chapel Hill
state: North Carolina
city: Cincinnati
country: United States
facility: Children's Hospital, Cincinnati Medical Center
state: Ohio
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: UT Health Houston
state: Texas
Study officials:
affiliation: Columbia University
name: Ronald Wapner, MD
role: PRINCIPAL_INVESTIGATOR
References: