Clinical trial NCT01336400: 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
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Preimplantation Genetic Diagnosis
Keywords: Single cell haplotyping
Preimplantation genetic diagnosis
Lead sponsor: Universitaire Ziekenhuizen KU Leuven
Sponsor class: OTHER
Collaborators: name: KU Leuven
name: Universitair Ziekenhuis Brussel
name: Vrije Universiteit Brussel
First posted: 2011-04-15
Enrollment: 60
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: We aim to collect spare embryos of 30 couples that opt for preimplantation genetic diagnosis (see Eligibility Criteria).

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.


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.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: Universitaire Ziekenhuizen Leuven
state: Vlaams Brabant
Study officials:
affiliation: Universitaire Ziekenhuizen KU Leuven
name: Joris R Vermeesch, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: KU Leuven
name: Thierry Voet, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Universitaire Ziekenhuizen KU Leuven
name: Thomas D'Hooghe, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: KU Leuven
name: Yves Moreau, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Vrije Universiteit Brussel
name: Karen Sermon, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Universitair Ziekenhuis Brussel
name: De Rycke Martine, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Vanneste E, Voet T, Le Caignec C, Ampe M, Konings P, Melotte C, Debrock S, Amyere M, Vikkula M, Schuit F, Fryns JP, Verbeke G, D'Hooghe T, Moreau Y, Vermeesch JR. Chromosome instability is common in human cleavage-stage embryos. Nat Med. 2009 May;15(5):577-83. doi: 10.1038/nm.1924. Epub 2009 Apr 26.
citation: Vanneste E, Voet T, Melotte C, Debrock S, Sermon K, Staessen C, Liebaers I, Fryns JP, D'Hooghe T, Vermeesch JR. What next for preimplantation genetic screening? High mitotic chromosome instability rate provides the biological basis for the low success rate. Hum Reprod. 2009 Nov;24(11):2679-82. doi: 10.1093/humrep/dep266. Epub 2009 Jul 24.