Copy Number AbnormalityNCT04285814
Technology Development for Noninvasive Prenatal Genetic Diagnosis Using Whole Fetal Cells From Maternal Peripheral Blood
An observational study of Copy Number Abnormality and Prenatal Diagnosis, run by Columbia University at 2 sites in United States.
Trial summary
Amniocentesis (amnio) and chorionic villus sampling (CVS) can reliably detect many smaller DNA/genetic abnormalities that cannot be reliably diagnosed by cell-free noninvasive prenatal testing (NIPT) that is in widespread use. Read more about this study
- Who is it for?
- Ages 18 years and older, women onlyHealthy volunteers can take part
- Conditions the study is for
- Copy Number Abnormality, Prenatal Diagnosis, Genetic Disease
- What is being tested?
- Whole Fetal Cell (WFC) Testing
- How many people
- 33 participants
- Where
- 2 sitesUnited States
- Study dates
- 1 Sep 2020to 20 Jul 2023
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- Healthy volunteers accepted
- Adult, Older adult
Study population: Pregnant women presenting at the study sites who have a karyotype and/or CMA performed will be recruited for this study. Half of the women will have a normal CMA (150) and half will have an abnormal CMA (150).
Who may be able to join
- Have already had a CVS or amniocentesis (blood sample collected >= 7 days after procedure).
- Have already received an abnormal (case) or normal (control) CMA/karyotype/FISH result from the CVS or amniocentesis.
Who cannot join
- Unavailability of maternal blood sample at least 7 days post-procedure.
- Language barrier (non-English or Spanish speaking and no adequate interpreter)
- Maternal age of less than 18 years
- Higher order multiple pregnancy (triplet or greater)
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Baylor College of Medicine
Houston, Texas, 77030
Columbia University
New York, New York, 10032
About this study
Amniocentesis (amnio) and chorionic villus sampling (CVS) can reliably detect many smaller DNA/genetic abnormalities that cannot be reliably diagnosed by cell-free noninvasive prenatal testing (NIPT) that is in widespread use. The investigators present evidence that a cell-based form of NIPT, here called Single Fetal Cell (SFC) testing, using a blood sample from the mother can detect most or all of the genetic abnormalities that are detected using amnio or CVS. This study proposes to compare the effectiveness of SFC testing in detecting abnormalities already detected by amnio or CVS in women already undergoing these tests as part of their clinical care because of fetal ultrasound abnormalities.
Read the detailed description
This is a revision to a project entitled "Prenatal Genetic Diagnosis by Genomic Sequencing: A Prospective Evaluation." This study proposes to test the utility and accuracy of a new form of cell-based noninvasive prenatal testing (NIPT), here called noninvasive Single Fetal Cell (SFC) testing. After many years of development work, the researchers published evidence for the feasibility of SFC testing in 2016. Extensive recent preliminary data show considerable improvements in SFC testing. Current forms of cell-free NIPT testing do not provide reliable detection of medium to smaller size deletions and duplications that cause a variety of genetic disabilities. Preliminary data indicate that SFC testing using fetal trophoblasts from mother's blood can detect aneuploidy and subchromosomal deletions and emphasize the importance of analyzing single cells, since some fetal cells are apoptotic and some are in S phase of the cell cycle replicating their DNA. Both apoptosis and S phase interfere with copy number analysis in differing ways, and pooling cells prior to barcoding individual cells results in loss of data quality. Preliminary data from two pilot validation studies demonstrate that reliable data can be collected on the large majority of patients, although data on this point would be greatly expanded by this project.
Preliminary data show very robust detection of all aneuploidies and clear definition of genomic deletions as small as 1 Mb and duplications as small as 1.5 Mb. The first aim is to perform blinded SFC testing on 50 cases per year with congenital anomalies with abnormal karyotype or chromosomal microarray (CMA) and 50 cases per year with congenital anomalies and normal CMA. This will provide a direct measure of success rate and the false positive and false negative rates for SFC testing compared to CMA. The second aim will be to use the WGA products and frozen unamplified cells available from aim 1 to further improve SFC testing to include targeted detection of inherited or de novo pathogenic point mutations in the cases undergoing WGS as part of the parent grant, confirmation of very small CNVs detected by WGS, restudy of false positive or false negative results from aim 1, and in the future could attempt to perform genome wide detection of de novo mutations. Capitalizing on the resources available through the parent grant, there is the opportunity to test whether SFC testing has the potential to transform genetic prenatal diagnosis so that all genetic changes, whether CNV or point mutation, and whether inherited or de novo, could be detected even in low risk pregnancies.
- Conditions
- Copy Number Abnormality, Prenatal Diagnosis, Genetic Disease
- Being tested
- Whole Fetal Cell (WFC) Testing
- Keywords
- noninvasive prenatal testing, microarray, fetal cells, prenatal diagnosis
- Medical subject headings
- Genetic Diseases, Inborn
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Whole Fetal Cell (WFC) TestingDiagnostic test
Performing WFC testing on blood specimens.
| Study group | Role | What they receive |
|---|---|---|
| Normal CMA | 150 women whose blood samples will be drawn for WFC testing who previously had a CMA performed with normal results. Receives: Diagnostic Test: Whole Fetal Cell (WFC) Testing | |
| Abnormal CMA | 150 women whose blood samples will be drawn for WFC testing who previously had a CMA performed with abnormal results. Receives: Diagnostic Test: Whole Fetal Cell (WFC) Testing |
What is being measured
The primary outcome is the main question the study is designed to answer.
Using a population of pregnancies with abnormal and normal karyotypes and CMAs, determine the false positive, false negative, true positive, and true negative rates of WFC testing.
Measured: 3 years
Determine the technical success rate for WFC testing including number of scorable cells for each sample.
Measured: 3 years
Determine the level of resolution for detecting deletions/duplications by WFC testing based on "spiked in" samples of known CNVs and on analysis of naturally occurring CNVs in fetal cells.
Measured: 3 years
Determine capability and success rate for genotyping single gene mutations including de novo and inherited single gene mutations and benign SNPs.
Measured: 3 years
Secondary outcomes (3)
Evaluate WFC testing results according to gestational age at testing, specific anomalies, maternal weight, and multiple gestations.
Measured: 3 years
Determine whether cells are more frequent in pregnancies resulting in adverse pregnancy outcomes including preeclampsia.
Measured: 3 years
Improve methods for genotyping single cells including ability to perform genotyping and genome-wide copy number analysis on the same cell.
Measured: 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Feb 2020
- Study start1 Sep 2020
- Primary completion20 Jul 2023
- Study completion20 Jul 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Copy Number AbnormalityStudies of the same condition, open and under way.
- More trials run by Columbia UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 33 participants (actual)
Sponsor and investigators
- Lead sponsor
- Columbia University
- Sponsor type
- University, hospital or other
- Collaborators
- Baylor College of Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Responsible party
- Principal investigator, Ronald J Wapner, MD, Columbia University
- Investigators
- Ronald Wapner, MD, Principal investigator, Columbia University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04285814
- Sponsor's protocol ID
- AAAS9107
- Other IDs
- 3R01HD055651
- Status last verified
- Jan 2025
- First submitted
- 24 Feb 2020
- Last updated
- 29 Jan 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: The project dataset and associated genomic data be widely shared with the scientific community for research through the controlled access dbGAP repository or comparable databases while carefully observing standards of patient privacy, confidentiality, and management of health information complying with the NIH Genomic Data Sharing policy. The data-sharing of genetic data will be in dbGaP. Data will be generated in all years of the study and submitted at study completion. Resources including study protocols, informed consent templates, result report templates and bioinformatic tools will also be made available through open access databases and public web sites. We will make datasets and informatics tools available through approved platforms for sharing with the larger scientific community. We will store remaining DNA samples with permission to use these samples for future research related to WFC. These specimens will be stored in a coded fashion.
Study at a glance
From the registry record, last updated by the sponsor on 29 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Technology Development for Noninvasive Prenatal Genetic Diagnosis Using Whole Fetal Cells From Maternal Peripheral Blood
- ClinicalTrials.gov ID
- NCT04285814
- Acronym / sponsor ID
- AAAS9107
- Conditions
- Copy Number Abnormality, Prenatal Diagnosis, Genetic Disease
- Keywords
- noninvasive prenatal testing, microarray, fetal cells, prenatal diagnosis
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 33 participants (actual)
- Lead sponsor
- Columbia UniversityUniversity, hospital or other
- Collaborators
- Baylor College of Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Study start
- 1 Sep 2020 (actual)
- Primary completion
- 20 Jul 2023 (actual)
- Study completion
- 20 Jul 2023 (actual)
- First posted
- 26 Feb 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Amniocentesis (amnio) and chorionic villus sampling (CVS) can reliably detect many smaller DNA/genetic abnormalities that cannot be reliably diagnosed by cell-free noninvasive prenatal testing (NIPT) that is in widespread use. The investigators present evidence that a cell-based form of NIPT, here called Single Fetal Cell (SFC) testing, using a blood sample from the mother can detect most or all of the genetic abnormalities that are detected using amnio or CVS. This study proposes to compare the effectiveness of SFC testing in detecting abnormalities already detected by amnio or CVS in women already undergoing these tests as part of their clinical care because of fetal ultrasound abnormalities.
Detailed description
This is a revision to a project entitled "Prenatal Genetic Diagnosis by Genomic Sequencing: A Prospective Evaluation." This study proposes to test the utility and accuracy of a new form of cell-based noninvasive prenatal testing (NIPT), here called noninvasive Single Fetal Cell (SFC) testing. After many years of development work, the researchers published evidence for the feasibility of SFC testing in 2016. Extensive recent preliminary data show considerable improvements in SFC testing. Current forms of cell-free NIPT testing do not provide reliable detection of medium to smaller size deletions and duplications that cause a variety of genetic disabilities. Preliminary data indicate that SFC testing using fetal trophoblasts from mother's blood can detect aneuploidy and subchromosomal deletions and emphasize the importance of analyzing single cells, since some fetal cells are apoptotic and some are in S phase of the cell cycle replicating their DNA. Both apoptosis and S phase interfere with copy number analysis in differing ways, and pooling cells prior to barcoding individual cells results in loss of data quality. Preliminary data from two pilot validation studies demonstrate that reliable data can be collected on the large majority of patients, although data on this point would be greatly expanded by this project.
Preliminary data show very robust detection of all aneuploidies and clear definition of genomic deletions as small as 1 Mb and duplications as small as 1.5 Mb. The first aim is to perform blinded SFC testing on 50 cases per year with congenital anomalies with abnormal karyotype or chromosomal microarray (CMA) and 50 cases per year with congenital anomalies and normal CMA. This will provide a direct measure of success rate and the false positive and false negative rates for SFC testing compared to CMA. The second aim will be to use the WGA products and frozen unamplified cells available from aim 1 to further improve SFC testing to include targeted detection of inherited or de novo pathogenic point mutations in the cases undergoing WGS as part of the parent grant, confirmation of very small CNVs detected by WGS, restudy of false positive or false negative results from aim 1, and in the future could attempt to perform genome wide detection of de novo mutations. Capitalizing on the resources available through the parent grant, there is the opportunity to test whether SFC testing has the potential to transform genetic prenatal diagnosis so that all genetic changes, whether CNV or point mutation, and whether inherited or de novo, could be detected even in low risk pregnancies.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Normal CMA | – | Diagnostic Test: Whole Fetal Cell (WFC) Testing150 women whose blood samples will be drawn for WFC testing who previously had a CMA performed with normal results. |
| Abnormal CMA | – | Diagnostic Test: Whole Fetal Cell (WFC) Testing150 women whose blood samples will be drawn for WFC testing who previously had a CMA performed with abnormal results. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- Pregnant women presenting at the study sites who have a karyotype and/or CMA performed will be recruited for this study. Half of the women will have a normal CMA (150) and half will have an abnormal CMA (150).
Key inclusion criteria (2 listed)
- Have already had a CVS or amniocentesis (blood sample collected >= 7 days after procedure).
- Have already received an abnormal (case) or normal (control) CMA/karyotype/FISH result from the CVS or amniocentesis.
Key exclusion criteria (4 listed)
- Unavailability of maternal blood sample at least 7 days post-procedure.
- Language barrier (non-English or Spanish speaking and no adequate interpreter)
- Maternal age of less than 18 years
- Higher order multiple pregnancy (triplet or greater)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Whole Fetal Cell (WFC) TestingPerforming WFC testing on blood specimens. | Diagnostic test | Abnormal CMA, Normal CMA |
Primary outcome
Using a population of pregnancies with abnormal and normal karyotypes and CMAs, determine the false positive, false negative, true positive, and true negative rates of WFC testing.
Time frame: 3 years
Determine the technical success rate for WFC testing including number of scorable cells for each sample.
Time frame: 3 years
Determine the level of resolution for detecting deletions/duplications by WFC testing based on "spiked in" samples of known CNVs and on analysis of naturally occurring CNVs in fetal cells.
Time frame: 3 years
Determine capability and success rate for genotyping single gene mutations including de novo and inherited single gene mutations and benign SNPs.
Time frame: 3 years
3 secondary outcomes
Evaluate WFC testing results according to gestational age at testing, specific anomalies, maternal weight, and multiple gestations.
Time frame: 3 years
Determine whether cells are more frequent in pregnancies resulting in adverse pregnancy outcomes including preeclampsia.
Time frame: 3 years
Improve methods for genotyping single cells including ability to perform genotyping and genome-wide copy number analysis on the same cell.
Time frame: 3 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Jan 2025.
- Individual participant dataSharing planned: No. The project dataset and associated genomic data be widely shared with the scientific community for research through the controlled access dbGAP repository or comparable databases while carefully observing standards of patient privacy, confidentiality, and management of health information complying with the NIH Genomic Data Sharing policy. The data-sharing of genetic data will be in dbGaP. Data will be generated in all years of the study and submitted at study completion. Resources including study protocols, informed consent templates, result report templates and bioinformatic tools will also be made available through open access databases and public web sites. We will make datasets and informatics tools available through approved platforms for sharing with the larger scientific community. We will store remaining DNA samples with permission to use these samples for future research related to WFC. These specimens will be stored in a coded fashion.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ronald Wapner, MD principal investigator
Columbia University
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Copy Number Abnormality and Prenatal Diagnosis, run by Columbia University at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Using a population of pregnancies with abnormal and normal karyotypes and CMAs, determine the false positive, false negative, true positive, and true negative rates of WFC testing. (time frame: 3 years). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Jan 2025.