Prenatal Genetic Diagnosis by Genomic Sequencing

Columbia University1,097 enrolled

Overview

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.

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

1,097

Conditions

Fetal Structural Anomalies

Interventions

Prenatal Genomic SequencingDIAGNOSTIC_TEST

Whole genome sequencing (which initially will be masked and reported as exome only)

Eligibility

Sex: ALLMin age: 18 YearsHealthy volunteers:

Medical Language ↔ Plain English

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)

Locations (5)

Columbia University Medical Center

New York, New York, United States

University of North Carolina Chapel Hill

Chapel Hill, North Carolina, United States

Children's Hospital, Cincinnati Medical Center

Cincinnati, Ohio, United States

Baylor College of Medicine

Houston, Texas, United States

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: From time of diagnosis of anomaly to infant discharge

Secondary Outcomes

Gestational Age at Delivery

Gestational age of newborn at delivery (in weeks)

Time frame: 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.

Time frame: Up to 28 days after birth

Number of Deaths

Neonatal/infant death at time of discharge and at 12 months of age.

Time frame: 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.

Time frame: From discharge to 12 months postpartum

Length in Centimeters

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

UT Health Houston

Houston, Texas, United States

Infant length at 12 months of age.

Time frame: 12 months postpartum

Weight in Kilograms

Infant weight at 12 months of age.

Time frame: 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

Time frame: 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).

Time frame: 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).

Quality of Life by Self-report Questionnaire

Quality of life for the patient and family at 12 months postpartum.

Time frame: Approximately 4.5 years

QALY, Measured in Cost Per Year

Incremental cost per Quality Adjusted Life Year (QALY).

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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).

Time frame: 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.

Time frame: 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.

Time frame: 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).

Time frame: 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"

Time frame: 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.

Time frame: 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 frame: Time from sequencing initiation until study site result, up to 38 days