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

The recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years.
Verified April 2010 by Universitaire Ziekenhuizen Leuven.
Recruitment status was:  Not yet recruiting
Sponsor:
ClinicalTrials.gov Identifier:
NCT01336400
First Posted: April 15, 2011
Last Update Posted: April 15, 2011
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
Katholieke Universiteit Leuven
Universitair Ziekenhuis Brussel
Vrije Universiteit Brussel
Information provided by:
Universitaire Ziekenhuizen Leuven
  Purpose
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.

Condition Intervention
Preimplantation Genetic Diagnosis Other: single cell haplotyping

Study Type: Observational
Study Design: Observational Model: Case-Only
Time Perspective: Prospective
Official Title: Genome-wide Single Cell Haplotyping as a Generic Method for Preimplantation Genetic Diagnosis

Further study details as provided by Universitaire Ziekenhuizen Leuven:

Biospecimen Retention:   Samples With DNA
Genomic DNA, single blastomere DNA

Estimated Enrollment: 60
Study Start Date: October 2010
Estimated Study Completion Date: September 2013
Estimated Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
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
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.
PGD-PCR

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

-couples at risk for the transmission of monogenic diseases

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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Senior
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
We aim to collect spare embryos of 30 couples that opt for preimplantation genetic diagnosis (see Eligibility Criteria).
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.
  Contacts and Locations
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): NCT01336400


Contacts
Contact: Joris R Vermeesch, Professor +32 16 345941 Joris.Vermeesch@uzleuven.be
Contact: Thierry Voet, Professor +32 16 347991 Thierry.Voet@med.kuleuven.be

Locations
Belgium
Universitaire Ziekenhuizen Leuven Not yet recruiting
Leuven, Vlaams Brabant, Belgium, 3000
Contact: Joris R Vermeesch, Professor    +32 16 345941    Joris.Vermeesch@uzleuven.be   
Contact: Thierry Voet, Professor    +32 16 347991    Thierry.Voet@med.kuleuven.be   
Sponsors and Collaborators
Universitaire Ziekenhuizen Leuven
Katholieke Universiteit Leuven
Universitair Ziekenhuis Brussel
Vrije Universiteit Brussel
Investigators
Principal Investigator: Joris R Vermeesch, Professor Universitaire Ziekenhuizen Leuven
Principal Investigator: Thierry Voet, Professor Katholieke Universiteit Leuven
Principal Investigator: Thomas D'Hooghe, Professor Universitaire Ziekenhuizen Leuven
Principal Investigator: Yves Moreau, Professor Katholieke Universiteit Leuven
Principal Investigator: Karen Sermon, Professor Vrije Universiteit Brussel
Principal Investigator: De Rycke Martine, Professor Universitair Ziekenhuis Brussel