Preimplantation genetic diagnosis for haematologic conditions

This review will inform the clinician about the application, success rates and limitations of preimplantation genetic diagnosis (PGD) for haematologic disease to enable clinicians to offer couples with reproductive risk a realistic view of possible treatments. The molecular techniques used to diagnose disease mutations are described, including the newest technologies using whole genome amplification (WGA) and preimplantation genetic haplotyping (PGH) of embryos. The history and ethics involved in performing PGD together with human leukocyte antigen (HLA) testing (PGD-H) to create matched siblings suitable for haematopoietic stem cell transplant (HSCT) are discussed.

The greatest diagnostic hurdle in PGD is the paucity of molecular material in the single embryonic cell. WGA allows amplification of the entire genome, which greatly simplifies mutation analysis and increases the possibilities of multiple simultaneous genetic diagnoses. PGH can be applied to the amplified material, and may enable the application of PGD to the less common haematological mutations, and the diagnosis of nonaffected male progeny in cases of X-linked haematologic diseases.

PGD to exclude embryos carrying serious haematologic disease is a viable alternative to prenatal diagnosis for couples who wish to avoid having affected children and for whom therapeutic termination of affected pregnancies is unacceptable. PGD is not available for all haematologic mutations, is expensive, time consuming and does not guarantee a pregnancy. PGD-H is more diagnostically and ethically challenging, especially when there is the time constraint of urgent provision of HLA-matched stem cells for a sick sibling. To date there is only a handful of reported cases of successful HSCT from siblings created by embryo selection. The evolving technology of PGH following WGA may increase the diagnostic scope and availability of PGD in the future, but certain limitations will remain.