Preimplantation Genetic Diagnosis and Screening

If our patients have Southeast Asian ancestry, we should consider α-thalassemia (1 in 30), and for patients with Mediterranean ancestry, β-thalassemia. For patients of Ashkenazi Jewish ancestry, genetic screening is performed routinely for the ancestral mutations causing Tay-Sachs disease, familial dysautonomia, Gaucher's disease type 1, Niemann-Pick disease, Bloom syndrome, Canavan disease, and cystic fibrosis.

When we perform PGD, the testing is done overnight. Couples follow the same process that any infertile couple undergoing in vitro fertilization (IVF) would follow, but before implantation, a single cell is taken for analysis from each embryo in its day-3, eight-cell stage. The single-cell samples are sent by courier to a reference laboratory for overnight testing, and a report is electronically sent to the reproductive endocrinologist. Couples are notified of the results in time for embryo transfer on day 5.

In the future, we may be able to relax the timeline and allow more time for embryo transfer by performing the biopsies when the embryo is 5 days old. In this procedure, cells would be taken from the trophectoderm—the outer layer of the embryo that ultimately develops into the placenta—and the embryos would be frozen via a rapid freezing process called vitrification.

Ice crystals do not form in this method, so concerns about damage to the cells is alleviated. Women could then undergo embryo transfer the next month. For now, however, we follow a 5-day deadline for embryo transfer.

Regardless of what advances are made, we must appreciate the fact that this technology pushes medical diagnostics to its limits. PGD involves the testing of one single cell (the smallest unit of life) and one gene (the smallest unit of inheritance), for one typographical error in 3.3 billion DNA letters, and all of this occurs overnight.

Its Value and Accuracy

The nomenclature of what we have simply and rather loosely called PGD is actually changing a bit. Following Europe's lead, U.S. experts are beginning to use the term PGD to refer specifically to the actual diagnosis of a particular disease. PGS (preimplantation genetic screening) is exactly what its name implies as well—screening, largely for abnormal numbers of chromosomes—and not the actual disease diagnosis. Together, the terms fall under the general rubric of preimplantation genetics.

The differentiation is being made because everything about the two procedures—the technology; the people and issues involved; the risks and benefits; and importantly, the accuracy of the procedure—is different. All told, the error rate for preimplantation genetics is in the range of about 2%–4%. Analyzing chromosomes, however, is quite different from analyzing genes, just as counting books of the encyclopedia is quite different from opening a book and finding a letter error.

In analyzing chromosomes, we have to worry about the possibility of complex chromosomal mosaicism having occurred. This is a process by which chromosomes segregate unevenly to cells as the cells are dividing, and if it has occurred, some of the cells we biopsy may appear normal even though the rest of the cells are not.

Experts are increasingly concerned that the chromosome analysis component of preimplantation screening may not really be improving parents' chances of having a healthy baby. However, although the prognostic value of what we now should call PGS is unclear and confusing, there are no such doubts associated with PGD. Telling parents that their baby has a clear 25% chance of having a serious disease is quite different from telling parents that their baby may—or may not—have a chromosomal abnormality.

This is not to say, however, that PGS is without value. I would advise it in cases in which the woman already needs IVF and if she has had recurrent miscarriages.

Ethical Issues and the Future

The real issue with preimplantation genetics, I believe, is whether there are limits to when the technology can and should be used. We must continue, of course, to consider and address the questions associated with PGS and its value. But beyond this, we face numerous questions emanating not as much from a scientific or technologic perspective as from an ethical perspective.

For instance, couples who already have a child with a genetic disease and do not want it to happen again can test their embryos not only to learn which ones carry the genetic defect, but also to learn whether any of their embryos are an identical stem-cell match with their child who is ill.

At the time of delivery, then, they will have not only a healthy baby, but also a baby who can donate identically human leukocyte antigen (HLA)-matched cord blood for stem-cell transplantation to the sibling. Such testing for HLA matching happens daily in the United States.