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Genome-wide Single Cell Haplotyping as a Generic Method for Preimplantation Genetic Diagnosis

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ClinicalTrials.gov Identifier: NCT01336400
Recruitment Status : Unknown
Verified April 2010 by Universitaire Ziekenhuizen Leuven.
Recruitment status was:  Not yet recruiting
First Posted : April 15, 2011
Last Update Posted : April 15, 2011
Sponsor:
Collaborators:
KU Leuven
Universitair Ziekenhuis Brussel
Vrije Universiteit Brussel
Information provided by:
Universitaire Ziekenhuizen Leuven

Tracking Information
First Submitted Date April 13, 2011
First Posted Date April 15, 2011
Last Update Posted Date April 15, 2011
Study Start Date October 2010
Estimated Primary Completion Date September 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures Not Provided
Original Primary Outcome Measures Not Provided
Change History No Changes Posted
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Genome-wide Single Cell Haplotyping as a Generic Method for Preimplantation Genetic Diagnosis
Official Title Genome-wide Single Cell Haplotyping as a Generic Method for Preimplantation Genetic Diagnosis
Brief Summary The investigators previously developed approaches to SNP-, CNV- and haplo-type single human cells (Vanneste et al. 2009, Nature Medicine). These methods open the possibility to be developed into a novel generic diagnostic technique which broadens the spectrum of disease-alleles that can be selected against during preimplantation genetic diagnosis (PGD) and which enables to help those couples that cannot be supported by PGD yet. PGD is the genetic analysis of a single blastomere from an in vitro fertilized (IVF) embryo and it is offered to couples to avoid the transmission of heritable genetic disorders to their offspring. PGD analyses are performed for (1) autosomal dominant or recessive monogenic diseases, (2) X-linked disorders and (3) chromosomal aberrations that may result in aneuploid conceptions. This novel method is likely to outperform and hence, replace current techniques for preimplantation genetic diagnosis. In this project the investigators will bring the technology from a proof-of-principle to the clinical application. To this end the investigators will make computational improvements for accurate single blastomere SNP-, CNV- and haplo-typing and perform a large validation study. For the validation studythe investigators will analyse the genomes of the blastomeres derived from 60 spare embryos of different origin: (1) Embryos diagnosed as genetically abnormal using current PCR- and FISH-protocols. (2) Embryos diagnosed as normal for the investigated region using current PCR- and FISH-protocols, but not of sufficient quality to be transferred or frozen. (3) Embryos of the sex that is selected against following PGD based sex-selection, or embryos of the sex that is selected for but of insufficient quality to be transferred or frozen. (4) Embryos that were not biopsied in a PGD cycle since they suffer a slight growth delay. This validation study will allow us to evaluate (1) the clinical validity (false positive and negative rate) and (2) clinical applicability (in terms of ease of use, success rate, etc.). In addition, it will bring us essential further fundamental insights in the origins and mechanisms of chromosomal instability operating during early embryogenesis and its consequences for clinical applications of PGD. Finally, following the validation study, this project will clinically implement the technique to treat 10 families.
Detailed Description Not Provided
Study Type Observational
Study Design Observational Model: Case-Only
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
Genomic DNA, single blastomere DNA
Sampling Method Probability Sample
Study Population We aim to collect spare embryos of 30 couples that opt for preimplantation genetic diagnosis (see Eligibility Criteria).
Condition Preimplantation Genetic Diagnosis
Intervention Other: single cell haplotyping
We aim to collect single blastomeres from spare IVF embryos of 30 couples to optimize and test methods for single cell haplotyping. We aim to collect 20 and 10 couples coming to the fertility centre for FISH- or PCR-based PGD respectively. In both groups, at least 5 different indications for PGD will be collected. Per couple, we will perform 10 SNP-arrays: 2 for the couple donating the embryo, 4 for family members (often parents of the couple) and 4 for blastomeres since we aim to pick 2 cells from 2 embryos per couple. For five couples, 2 blastomeres of all available embryos will be aspirated to validate and optimize the phasing methods. Finally, for some embryos, all blastomeres will be picked to be able to prove the reproducibility of single cell haplotyping.
Study Groups/Cohorts
  • PGD-FISH

    Following couples opting for preimplantation genetic diagnosis on the basis of FISH:

    • couples suffering a complex chromosomal rearrangement (CCR)
    • couples with X-linked recessive disorders
    • couples that carry a balanced chromosomal rearrangement
    Intervention: Other: single cell haplotyping
  • PGD-PCR

    Following couples opting for preimplantation genetic diagnosis on the basis of PCR:

    -couples at risk for the transmission of monogenic diseases

    Intervention: Other: single cell haplotyping
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Unknown status
Estimated Enrollment
 (submitted: April¬†14,¬†2011)
60
Original Estimated Enrollment Same as current
Estimated Study Completion Date September 2013
Estimated Primary Completion Date September 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

Blastomeres biopsied from spare embryos ((A) Embryos diagnosed as genetically abnormal using current PCR- and FISH-protocols; (B) Embryos diagnosed as normal for the investigated region using current PCR- and FISH-protocols, but not of sufficient quality to be transferred or frozen; (C) Embryos of the sex that is selected against following PGD based sex-selection, or embryos of the sex that is selected for but of insufficient quality to be transferred or frozen; (D) Embryos that were not biopsied in a PGD cycle since they suffer a slight growth delay.) derived from following patient groups:

  1. The first patient group involve couples suffering a complex chromosomal rearrangement (CCR), which is defined as a structural chromosomal rearrangement with at least three breakpoints and an exchange of genetic material between two or more chromosomes.
  2. The second patient group involve couples with X-linked recessive disorders.
  3. The third patient group consists of couples that carry a balanced chromosomal rearrangement - a translocation, insertion or inversion - that may result in recurrent miscarriage or aneuploid, severely handicapped offspring.
  4. A fourth patient group are couples at risk for the transmission of monogenic diseases.
Sex/Gender
Sexes Eligible for Study: All
Ages Child, Adult, Older Adult
Accepts Healthy Volunteers No
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries Belgium
Removed Location Countries  
 
Administrative Information
NCT Number NCT01336400
Other Study ID Numbers IWT-TBM-090878
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Professor Joris Vermeesch, Universitaire Ziekenhuizen Leuven
Study Sponsor Universitaire Ziekenhuizen Leuven
Collaborators
  • KU Leuven
  • Universitair Ziekenhuis Brussel
  • Vrije Universiteit Brussel
Investigators
Principal Investigator: Joris R Vermeesch, Professor Universitaire Ziekenhuizen Leuven
Principal Investigator: Thierry Voet, Professor KU Leuven
Principal Investigator: Thomas D'Hooghe, Professor Universitaire Ziekenhuizen Leuven
Principal Investigator: Yves Moreau, Professor KU Leuven
Principal Investigator: Karen Sermon, Professor Vrije Universiteit Brussel
Principal Investigator: De Rycke Martine, Professor Universitair Ziekenhuis Brussel
PRS Account Universitaire Ziekenhuizen Leuven
Verification Date April 2010