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Prenatal Cytogenetic Diagnosis by Array-Based Copy Number Analysis (Microarray)

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ClinicalTrials.gov Identifier: NCT01279733
Recruitment Status : Completed
First Posted : January 19, 2011
Last Update Posted : August 22, 2012
Sponsor:
Collaborator:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Ronald J Wapner, MD, Columbia University

Study Description
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Brief Summary:
The main objective of the multi-centered collaborative study is to evaluate the accuracy, efficacy and clinical advantages of prenatal diagnosis using microarray analysis as compared with conventional karyotyping.

Condition or disease Intervention/treatment
Genetic Diseases Genetic: Microarray analysis

Detailed Description:

Specifically, the aims are as follows:

  1. Demonstrate the performance of microarray analysis as a clinical method for prenatal cytogenetic diagnosis with regard to:

    1. Accuracy in the detection of the common autosomal and sex chromosomal aneuploid (trisomies, 13,18,21, 45,X, 47,XXY, etc.)
    2. Ability of microarray to diagnose less common, but clinically significant, cytogenetic aneusomies (e.g. DiGeorge, Williams, Smith- Magenis, Prader-Willi syndrome, etc.) currently not detected by conventional karyotype.
    3. Evaluation of the utility of microarray in specific clinical scenarios such as ultrasound detection of congenital anomalies and fetal growth disorders.
  2. Evaluate the appropriate construction of prenatal diagnostic microarray devices to allow maximal detection of clinically relevant information with minimal detection of unexpected and difficult to interpret findings which have no clinical significance but might provoke patient anxiety.
  3. Evaluate the feasibility and cost-effectiveness of using microarrays as a primary prenatal diagnostic tool.
  4. Evaluate approaches to integrate microarray into clinical prenatal cytogenetic diagnostic practice.
  5. Develop a prenatal diagnostic tissue repository (TDR) to facilitate the further development of microarray technology. This will be used to investigate the molecular etiologies of specific fetal anomalies and to test newer technologies, such as higher resolution microarrays.
Study Design
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Study Type : Observational
Actual Enrollment : 4450 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Prenatal Cytogenetic Diagnosis by Array-Based Copy Number Analysis
Study Start Date : October 2008
Actual Primary Completion Date : October 2011
Actual Study Completion Date : October 2011
Groups and Cohorts
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Group/Cohort Intervention/treatment
Microarray Analysis Genetic: Microarray analysis

Microarray performed on prenatal specimen:

Fluorescence in-situ hybridization (FISH) or other standardized tests such as qPCR or MLPA will be performed on the fetal sample to confirm abnormal MA findings of known and unknown clinical significance which are discordant with CC findings, including anomalies normally detected by karyotyping.

Microarray analysis of DNA from parental blood samples will be used to determine whether CNVs detected in a fetal sample are also present in a healthy parent, in which case no further evaluation will take place, moreover any finding in a fetus which is duplicated in a parental microarray is considered to be confirmed.


Outcome Measures
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Primary Outcome Measures :
  1. Detection rate of fetal cytogentic abnormalites between microarray copy number analysis and karyotype in prenatal samples [ Time Frame: Up to 2.5 years after recruitment of 4400 patients. ]
    This is a blinded prospective comparison of microarray copy number analysis to metaphase karyotyping for the detection of common fetal cytogentic abnormalites


Secondary Outcome Measures :
  1. The ability of microarray copy number analysis to identify clinically significant microdeletions and duplications not seen by standard karyotyping [ Time Frame: Up to 2.5 years . ]
    This outcome will identify the frequency of clinically significant microdeletions and microduplications that are identified on microarray CNA that were not seen on the clinical karyotype. Only copy number variants over 1 Mb in the backbone and those in predesignated critical regions will be included

  2. The rates of clinically significant copy number variants associated with specific prenatal conditions [ Time Frame: Up to 2.5 years after recruitment of 4400 patients. ]
    THe frequency of clinically significant copy number variants in cases with fetal anomalies, advanced maternal age, positve serum screening, and fetal growth disorders will be determined.


Biospecimen Retention:   Samples With DNA
  • Additional 15 ml of amniotic fluid (minimum 10 ml) for amniocentesis
  • Blood sample (10 ml) from each parent will be obtained in case of a need to test for suspected familial copy number variants (CNVs) or discrepant results, and also to evaluate for maternal cell contamination (patient's blood sample).
  • 10 ml of amniotic fluid with suspended cells, (minimum 7 ml)
  • 5 mg of villi (minimum of 2mg)

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
A total of 4,400 prenatal diagnostic samples will be obtained from patients undergoing prenatal testing for standard indications. Patients will be recruited at participating prenatal diagnostic centers by designated study personnel; recruitment of patients will be initiated as a pilot study. These patients will not contribute to the final planned sample size of 4400 patients. Two sub-studies will then be initiated consisting of 250 (or more) patients enrolled with sufficient amniotic fluid sample and 250 (or more) patients with sufficient villus sample.
Criteria

Inclusion Criteria:

  1. Singleton pregnancy having either chorionic villus sampling in the first trimester or an amniocentesis procedure at or after 16 weeks of gestation performed for prenatal cytogenetic diagnosis
  2. Karyotyping to be performed at Genzyme Genetics Cytogenetics Laboratory
  3. Trained study personnel available
  4. Presenting at pre-specified sites using Genzyme Genetics for routine prenatal diagnostic services

Exclusion Criteria:

  1. Unavailability of one or both biologic parents to provide blood sample (e.g. egg or sperm donor, non-paternity)
  2. Patient refusal to allow follow-up through the neonatal period and up to age two if selected
  3. Participation in the study in a previous pregnancy
  4. Insufficient sample for microarray assay
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01279733


Locations
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United States, New York
Columbia University Medical Center
New York, New York, United States, 10032
Sponsors and Collaborators
Columbia University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
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Principal Investigator: Ronald Wapner, MD Columbia University
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Ronald J Wapner, MD, Professor of Obstetrics & Gynecology, Columbia University
ClinicalTrials.gov Identifier: NCT01279733    
Other Study ID Numbers: AAAC8036
1R01HD055651-01 ( U.S. NIH Grant/Contract )
First Posted: January 19, 2011    Key Record Dates
Last Update Posted: August 22, 2012
Last Verified: August 2012
Keywords provided by Ronald J Wapner, MD, Columbia University:
microarray
Additional relevant MeSH terms:
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Genetic Diseases, Inborn