Official Title
Prenatal Genetic Diagnosis by Genomic Sequencing: A Prospective Evaluation
Brief Title
Prenatal Genetic Diagnosis by Genomic Sequencing
Protocol ID
NCT03936101
Lead Sponsor
Columbia University
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 Period
-
Enrollment Count
1,097 participants
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)
Filters
Fetal Structural Anomalies
COMPLETED
ADULT
OLDER_ADULT