Array informatics to understand ploidy concordance

DESCRIPTION (provided by applicant): In each IVF cycle, a decision must be made as to which embryo(s) will be selected for transfer. This decision has a far reaching impact on the outcome of an IVF cycle, namely whether the embryo will develop into a healthy child. It is estimated that at least 50% of human embryos are affected by chromosomal abnormalities such as aneuploidy, and implantation of such embryos can lead to undesired outcomes such as failed implantation, spontaneous abortion, or birth of a trisomic offspring. Reproductive specialists have been increasingly turning to pre-implantation genetic diagnosis (PGD) in efforts to identify embryos with the best chance of developing into healthy children. However, current techniques are expensive, unreliable and typically test only a small selection of chromosomes. GSN has developed an innovative technology termed Parental SupportTM (PS) whose output is an in silico reconstruction of the embryonic DNA at thousands of loci with confidence exceeding 99%. This technology will, for the first time, allow IVF physicians to screen embryos for chromosomal abnormalities including aneuploidy, translocations and deletions across all 23 pairs of chromosomes with an error rate below 0.1%. The Phase I objective of this application is to integrate our PS technology with a new, highly parallelized custom Infinium-based genotyping platform to dramatically reduce costs that will, in turn, enable GSN to offer PGD service with superior accuracy, scope and at a cost equivalent to current, less reliable FISH methods. The new customized platform will then be applied in Phase II where we propose to evaluate the concordance between a new trophectoderm biopsy technique on day 5, traditional blastomere biopsy on day 3, and the actual child. The results from these studies will allow us to assess the value of the new biopsy technique, evaluate the largely unstudied phenomenon of embryo self-correction between day 3 and day 5, and provide IVF physicians with powerful and far-reaching knowledge about the developmental potential of each embryo. PUBLIC HEALTH RELEVANCE: With the accumulating knowledge of how disease phenotypes are associated with genotypes, the question arises how this knowledge can be applied to improve the quality of life and health. Chromosomal disorders such as aneuploidy have been important causes of childhood morbidity and mortality, and the quality of life of the affected children will vary depending on which chromosome(s) is involved. In the context of in vitro fertilization (IVF), it is estimated that at least 50% of human embryos are affected by aneuploidy and other chromosomal abnormalities. Implantation of these embryos can lead to universally undesired medical outcomes such as failed embryo implantation, spontaneous abortion, or birth of a trisomic child. It is, therefore, not surprising that reproductive specialists are increasingly turning to preimplantation genetic diagnosis (PGD) testing in efforts to identify embryos with the best chance of development into healthy children. With this grant, Gene Security Network (GSN) will develop a new customized technology platform that integrates GSN's proprietary bioinformatics technology with Illumina-based genotyping technology. This customized platform will enable IVF physicians to screen embryos for aneuploidy, deletions, insertions and translocations across all chromosomes with unprecedented accuracy and scope, and at a similar cost compared to other methods. This technology, termed Parental SupportTM (PS), is built on the fundamental principles of meiosis and Human Genome Project data. In comparison to other existing PGD methods, GSN's new customized platform enables: i) determination of aneuploidy with roughly two orders of magnitude lower error rates; ii) determination of aneuploidy across all chromosomes; and iii) determination of aneuploidy simultaneously with common chromosomal deletions, insertions and translocations. GSN is developing the enhanced reporting system, statistical methods, and wet- lab infrastructure to offer this service to six of the leading IVF centers in the US (all of which have already signed letters of intent to purchase the service) and subsequently to the worldwide IVF community. Roughly 152,000 and 653,000 IVF cycles were performed in 2006 in the US and internationally, and PGD continues to grow at roughly 33% annually. In summary, funding for this study will enable GSN to design and develop a custom technology platform for simultaneous detection of aneuploidy, translocations, deletions, and insertions; validate the performance of the new technology; and apply the technology to investigate the utility of an emerging embryo biopsy technique. GSN's technology will bring the domain of embryo pre-implantation diagnosis into the realm of reliable diagnostics which can be regulated and used as part of the standard of care during in-vitro fertilization.